Cl inical Pharmacak inet ics Concepts and Application s third edition
MALCOlM ROWlAND, Ph.D. Depomnenr of Phormocy University of Iv\oncne$ler
fvlonchester, England
THOMAS N. TOZER, Ph.D. School of Pbcrmocv University of California
San Francisco, Cclnormc
A Leu ..v... Febiger Book
.e1~ LI pPINCOTT WILLIAMS & W ILKINS •
A Wollen Kluwef Company
Philadelphia • Ballimore • New York • l ondon Buenos Aires • Hong Kong . Syd ney • Tokyo
f:.w .: uIIH'
f:.I.,,,,, !)""'..l H
11tlO-It'/>f'U" Ud l l.;.[I/.-n Frmu.·#"! I-: li tu, I.L<{;i :'>tnl<1 ' .....1....·' ''',., .u.....lR"...
u. urw.· Ft>¥'$J1h
f 'n:>J«t /-:.111"" J(oh." lJ .1I('1tt,·
Copyright C I99S
lW
~r, lI ..m.
HO ~·01
l!< ~'i u.,; ...
~ .....
Pt"l.Jdrh'" lm yInft .. 1'1101'>-:1021 l ' !>A
All ri¢lt~ re....'rve·d Thi~ h<.. .. i.~ I'rul~-..:1•..J I')' cnpy ril(ht , . .." p;ln (>t lhi~ h•• ok lIu)' I... n.· pr"du...·tI in "n y '.. rm nr tl)' ..n)' rnt~"Il-~. ind ud mjt ph'lIu':OPyinll. 0' ulllll.et.l hy ~n)' infum u lion "" "'-"11<' ~n<.I 1'1.1,...·,..,,1 ~)·", .-n l .....i1huu l ....Titl.-n pemli.,~i"n (ru m lho.- n ,p\.-rixh! . ..... I'll·r An'Ur~l .. inlJiGlli(>n~. ~.h'ff'>t" ll.·oI<.1i< ...~. ~oo J<"..;I!lt' ·hnluk-" fur drull" an.' pt<" i<.k'
f i~ UrwnllO ·it.....' lhe.- p;ld.,.:.lJC" infun1l.llKlf1 wI" ..r II... nunub'1u ...." (lr lho.- mnli<.~ I IIl"'~ rnt'1l1K>nnJ.
I'firllcd in 11M:' l :nit ..-d Sl"l..,.. , rl Anlt"fit'
Ubnry or CAm~ Cata",-"" ln K-ln ·Puh llc a don Dala Itu..... boo. 1t-f.l.kolm, O in i<'f B.."k .~
Ind u<1o:-!< hihli<'Ilf'lphi<.·..1 n..rl·n..I'll~"oo Indo-·" . ISUS ().(1Mj-(J7i(~·O 1 Plunruc" killt1 it'!o l Cho(.-nKJlhlT~J')·, TOIt·r. l1K1flU' S ,
n. nne. lu s U.t 1. Plunrun okllw:iio k.\1~1I .~ .R6K
l .Im..1l Th<.T.. p)·
Q V .\Ii llSK;k 1....,1-11
,~
6 1".7_k lO ' ) ~ L\ L ,() LC
fur lihr~rr .. t CA IOIlft"'"
"Ie.,.,. 10'" I" ..... I " ..1I•."..1 1/lhory-' 1><'/1' ill ·t"Ui' .,· (lm"lRt 'm",,',~ (.1 Iht·fiN o(>(>"rr" "'1l'
Iht- /'"hlu/l<111' ...... 1<. ",.ory .tJi,rr 1'-' Irw.·.. lho-' ·''''.I'tlNbl h.. 'l
>U••
9 10
PREFACE PURPOSE 01 TIXT kt 't' pill~ wtth tilt' fi o t hm ("l;lilions. is a pn nu-r in p harmacokinet ics clhucn l applica tions. 111t' Ix)ok should hl' useful to ilny student. pmc· tulom-r. o r rt'sl'ard lt'r Willi is in f('rt'slt'() o r t 'llga~("ll in til(' dt ·" dopllll'u t , e-....uluutk rn. o r II!\('
The rhin l l"tlitioll. in
\\i th a n
t' llI ph;l~i s 011
of nu-dn-im-s. SIl('h !W n;O Il S illdlldl' ph annac1sts. physicians. vete rinari ans. pharmaccuuca l scn-nt tsts. Im:ieo lo)..,'i sls, al1 al~1 i{Mu1chemists, luoc hennsts. and d ink'al chen us ts. It is a n in-
troduct ory text ami tln-n -fon - pn 'slllllt'S that tilt' n-ader Im." littll' or no t':qx' n t'IIl'(' O f k nowl( '(I~t· i ll lilt , an-a. Previous ('xposnn' 10 certain aspects of physioloK\' and pharmacclogy wo uld ht' 11I·lp(1I1, hilt it is 1101 ('Sst·utia!. SOIllt' kllowlt'( I~(· of calculus is also dt 'Sirab!e . Our intent h to ln-lp tilt' n-ader lenrn to apply plranuacokincncs in therape-utics . To this r-nd. W I ' I'lIlplJit\il l' {,(lIll,('pts t l ln )ll~h problem solving \\i th only til(' essence of requtr ed marlu-nuutcs . In tllis respect. til(' hook is a p ro~r.lI n m {'(II t'am inv; text. AI the bt";ll11i n ~ o f I';u: h d lapll'r, ohjt'(:liH's art' !-pH'n 10 itll'lltif)" lilt' s aln-nt poin ts 10 be learned . T o furt her aid in !e;ln-illl-: tln- man-rial. examples art' \\urkt'(! oul in del ail in tilt' text , At tilt' {'ud o f t·ad. chapter, t'Wl'pt tilt' first. then- an' problems thilt allo..... I!l1' reader to v;r...' p tilt' (,(JJl{" pts o f tilt' chapn-r ,Illd In lnukl 1)1\ man-rial ¢ H'n ill previ ous chapn-rs. nit' u n !t' r of tht, probk-ms in I'a('h cliapter n ·III'(1s cousuh-ratiou of both t1HIi(1111)' and how WI·I\ tlu- problems apply tn chapter principles . TIlt' questions sta rt wi th theless difli tult O Il('S and those thai t·. llplmsi...x- tlu- principh-s.
ORGANIZATION AND CONIINT As in tilt' s('('(md t'(lilioll , 11\1' I)( M)k is t!id t!('(1into fiv(' St,'<.1inllS: AbsUlVlion and Disl'll,).'i itinl\ Kim'lil'S. T ll{'raj'll,'lItil' Hl'¢Illt'nS, I'hysinlo¢ c COII('('pls and Knwttcs . Indhi tluali...at iou. ami SI'!l'(1t, ! Tnpil'S. T lmst' \\i sllinl-: to ~
CHANGES IN TNIRD EDITION T Il(' fl.y('a r ~a p hdw t"('11 tllis thinl ("(filion and tllP st,(,(lIld . puhlish,"(1 ill 19MJ. is shurt t'r tlla" tll(· 9 YI'af1i hd \\l ,,('U til(' st'(u nd alltl firo;l 1, litiol\s. nlis shUl1t·nillJ: o f tilt' Iilllt· spa n
Pl!EfACE
IM'tWl'i 'lI ,·d ilium rd ll'd s tln- l'\ l' r-J,:atl... rill ~ P,I( ~ ' of p" ~n'Ss alld a pplil'atioll of ehnical plla rllla(~lki ll d ics . D,"pill ' IlIi, J,:m\\11i. which Ila,\ n'( lllin "(l Ihe inclusion o f 1I111ch new ruatr-rial. ( '\('1"\' dfort Il,L' IM"( 'II matl(' lu (~lIIlaill tln- over all Si"A' of Ih.. book. This. in 11101, lias meant Ih,;1 SWill' lIlillt' rial llas lIad III Ix' ('o llde llS("(! or dd t'lt'(l. It IIlLs also n's1l11("( 1 ill a muc-h j,(n'all'r u,,' of "hhn ·"ia!ioll' . (·'I)(... · ial l~ for un its . T Ilt' 11I1I1l1M 'r . topn-, alit! S(" IUI'lll'(' of chapters have h('('11 kept ('Sst'lIl iall)" lilt" ~1 1Il (' ,L~ ill 11.1' \('('(Illd , -c Iiiion , IIIMl " I'r, r-ach chapter has b("('11 ('l\lt'nsi\"d )" n-visc..1 am l up(lalt"(! 10 I'IlSUf(' 111;(1 IIII' I',-,unpl,·\ n-lnn- 10 l1IITt'lIlly prescnlx-d dmg) , A part kul,lr (' Ilu rt h,L'; be-en IIMd,· III ind lill.' vtr-n.. It' I I I· lII i~ I T\. n,( ~~l1 i /il l C: Ihal Isomers ma v Imn ' dillen'nl kinet k-s and a(1i\ily. Tl l('n ' h "I"' l ('t>I I ~id('r,~!ioll o r til(" iJl(:n',l~ill~ Il llmh(·~ of IXllyp','pti d, ' am! protein dmj.(s ,·IlII·fJ..,'iIIl! [nun advances ill mol ecular hioJ, ~ and hiol ('('hlloll 'K\-" ' AItI Il)U~h the kiIwl k· (lllll",'ph an' lilt' sallw. 1111' phy, i ll lu'~i ~' halllllilll..:: of macmmoll'(11 lar comp ounds is ' lui'" dislilld from that of I ~pi('al slIIall lllol''(' lIlar \\t·it.:lll dm ~s . TIlt' pn-wutation of lilt' 1M10k h'LSa["'1IM'''II ruar]« .. I1 ~ illlprowd through Ih(' Ust· of (:olo r. TI ll' mort- nuportuut ("Illalions art- IIOW lIil..:lllighl1'd bv means of color. C hapter number ;111.1 ~'('1i' 1I 1 Ilt';\llillg IIlIWalllM 'a r al 1111 ' It Ip 'If ( '01(·11 p'I,l. ::" b~ nu! to assist ill (' mss- rt' fl· n' lIci ll ~ . .-\ lahll' of fn 'lllwnll.\ tN·d '~'llI buls hlL.. IIt·('1l pb( ~ "(II It 'I;lTt . Chapter 1 10 fad lil;lle n"tldillin ~ w mlltlk wln-n IH "~ 'S"IT\ ' . T he ralll.:1' alit! uumla -r of p robk-m-, al Ihe e ud of ('adl chapter and Appendix I (total o f ";7 III'W pruh[('Ill';) Ilan ' 1"'1'11 , " h, tallli,illy extem h-dto itssisl in 1('itm illlJ: p ruh l('m SU "; I1~ ill l)haTlna,~,ki lll 'l i('s , 'I(lsi Ill' lilt, addilillllal problem s an' taken Irmn hterutun-, rather than Sillllltt"'i!. Ib t" , T ilt, thtrd , -c [itiou (1J1llaill\ 102 IWW fig ures anti 20m'w tables, n:'l1('(1 in~, in large P;lrt . Ill,' atklllt'(', ilIad" ill n"t'('111 ~" ;I rs ill 11liT ~'ll lwll'(I~(· o f 111(' pharmacoknu-ttcs uf dn l~s . Tlnmun-rtal 0 11 "S mall \ 'UlllllW u f Di ~ 1 rihlltiull " thut compns,-d tilt' ttsl chapter of tilt' second ,..[itlon II '~~ 11t"('1I illlUTJMlTakti intn C l.aplt'r W . D istrihulioTl , atul :\ppc.·lIdh I-F. \\'1' (~llIlilllll ' 10 adopl a umfonu st'l of svmbols 11m! 10 II...• lIlilli.t.:r.ulIsIliIN (mwLl ,lS tlu vtaudard 1H,'aSl lW of couceutranon. \\'e do rt"l.1lj..'fli7'(·. however. tht· illl'n·,t\i llJl; trend towun ] tilt' atin plillil of 1lI0lM Illlil\ lind haw' pn l\itl'''tl a fad or for conversion ht'!"Wi'('1I tht· two lIllils of nu-acun-uu-nt ill til(' ('ll,'rt iIlPIlI fiWm· captious. \\'t' shall un l~' il(' convtnced of IIII' virt m- of ,,,I,,\y lISi ll~ lilt" molar s~"Sl p lIl of mcasun-ment wln-u dm ~s an' pn-scnlx-d in ~ Ild l Ilnih.
ACKNOWLEDGMENTS \\'1' \,;sh to th ank all tilt· Ulall)" silltipuls lind rea tlt·rs w!lu pn l\itl l"tl inpul thai Ilt'lp' ''lllis sha pt· Ihis Ihinl ("(!ilio n. Their 1·lllhIl Sia.SIIl ami {"m"llll r.t~{"IIWIlI haw ' 11t'('1l lIl,mlillllal st.ltln't· of salisfill1ion . To 111(' 1It'\.\· n·ilde r. Wt· hnpt· that 11... IItMlk \\i ll su('t.'t"("f. 1 in IlI'lpin~ ) U U
San
Fm'irl~('(J .
Calijonl;(/
\l a!t.1,lm H()\,·land l1 Ullll ll'i~ . T oz('r
CONTENTS Definition!> of St:ibols
xi
1. W hy C1inico l P ormocohnerics?
_
1
_
SIOION I. "'SORPTION AND DISPOSITION IINIHCS 2. Basic Ccn stde rcno ns
11
3 . Intravenous Dose
18
4 . Extravascular Dose
34
SlUION II. THIU'IUJI( IIGI.IN5 5 . Therapeutic Response and Toxicily 6 . Constant-Rote Reg imens 7 . M uhiple-Dose Regimens SECTION III.
8. 9. 10 . 11 . 12 .
53 66 83
PHYSIOLOGIC (ON((PTS AND IUUTI(S
I'v'lovement Through MemblOnes Absorption . Distribution Elimina tion Integration With Kinetics
SECTION IY.
10Q 1 19 137 156 184
INDIYIDUALlZATlON
13 . Variab ility 14 . Genetics 15 . AgeandWeighr 16 . Disease 17 . Interacting Drugs 18 . Concennctio n Monito,ing
203 220 230 248 267 290
.
SECTION Y. SEU CTE D TOPICS 19 . 20 . 2 1. 22 . 23 . 24 .
Distribution Kinetics Pharmaco logic Response MetabOlite Kinetics Dose and Time Dependencies TUfnovel Concep's .. , , Dialysis
.
SEUCTED lEADING APPIHDIX I. ADDITIONAL CONUPTS AND DUIYATIONS A . Assessment 01AUe B. Esnmct.on 01Eliminalion Hall·life flam Urine Dote
..
313 340 367 394 424
,44 3 463 469 .47 3
•
CCNTENf5
C . EstimaTion 01 Absorplion Kinetics F,om Plm mo Concentration DolO " .. ,."
478
D. f'.h:Jon Residence Time E. Amount of Drug in Body on Accumula tion
4 85
10 Plateau F. Oislribulion of Drugs Extensively Bound to Plasma Proteins "'
G B!cxxi 1o Plmmo C o oc eollO tjon Rolin H Esllmorion 01C,eohnine Clearance Under Nonsleody-Stote Conditions "rINDII II. IlIIlI.L X
uswn s [0 PlOIUMS
4 90 ,4 Q4
50 2 ..... 504
SOl - "110
586
DEFINITIONS OF SYMBOlS * Amoullt of dnl~ in hody. 1lI~ o r
A...
Amount of dnl ~ ill Ixxl)' at steady state.' during con stant -rate mt rave1I01lS in fusion , mg o r IJIllO]t' ,
A......
A\'erdge amount of dnlg in Ixxl)" during a dosing Interva l at ste ad}' state. mg or umole.
umolo. Atl
Alliount of t1nl~ at ubsorpnou n' m ai lli n~ tu he.' absorbed, 1ll~ o r "UIIO]t' .
sit(·
C UlIlulathl' amount of dnl~ I' Xe.'rd("(,1 U1l('h atl ~('t 1 in th(' urine, Ill~ Of j.tlllo le.
A d (", ) Amount of lllt'ta!xl iite
ellmtnan-d.
umole.
1lI~ or
CUlIllilati\'{' amount of dOl!,!: ex{·rt'h,,( ! ll n{' h;U1~(,,( !
in rlu- urme
A..,......: Mali:imu m and minimum amounts of dnlg in Ixx!y during a dosing Inte rval at sll'lld)" state on administering a fiu'tl dUM" at a fixl-c.1 dosing Interval, m~ o r
A..... ...
IJIIlO!t· ,
A....
dllrin~ a dusill ~ interva l at sh ';ldy
stun-,
111 ~ Of
umok-.
C umulative amount of d m~ ex(: rl"lt-c. I II Ile.·h;U1~t'tl in tilt' urille to lilllt' infinity aftN a ~i ll~!e duse ,
dust, at a fi\I-c.1 t1os in ~ Interval, Ill g O f umole.
AVC
Aft"a under the plasma drug con centration-nm e curve . Total un-a fmm tinll' () to infinity is implied unless the local ('(mt('lt indicates a specific time Interval. e .g,. dosing Interval, mg-hr/l , Of 1J~I . h r.
AVC"
To tal area under the blood dnlg concentrutio n timt· curve , mg-hr! L or p ~ l . hr .
mg or j.tmolt,. A (", )
Amount of md"hulilt ' in Ixx!y. 1Il ~ Of j.tll1ule.'. • TI\(' min imu m umouut o f dm ~ in Ixltly required to obtain " pn-detennim-dh-vcl o f n'spoII ~' , m ~ o r "U Il O!t ' .
A y ...... : ~l ll\i ll1 11 m am i nununum A,\',.."" amou nts of d m ~ in I)(ltly afh' r th e Xtil duSt, of fi.'H't! sin' ,wd ¢\"1'1I at a Iixed dosill~ interval , 1l1 ~ or
A UC(m )An 'illlm l('r tlw plasma rm-tabo-
lite co ncen tra tmn time curve. mg-h r/L or IJl\I ·hr .
AVC..
umoh-. "\\'.,
Amount o f dnl~ in I)(xly at tilllt' t aftN till· Xtli " O\t', 1Il~ Of umole. Amount of t1m ~ (t'maining to he t'xI'n'It-c.! ill umn- arkr a smglc dose-, mg or umole.
· C."..I ""iI' " n ' 10"''' .
Amount of drug in body at lillie t \\ithin a dosing Interval at stt·ady state O il ;u!millish'ring a fin-d
An'a under the plasma drug ( '( )IIcen tranon time cu rve within a dosing interval at steady state,
mg-hr/l . or
IJM -III'.
,\ V.\lC Total an-a under the first momont-time curve . mg-h.-2/L or 1J ~1 -1 1 .-2.
c
Co ncentration of dnl g ill plasma. mwL or j.t ~ 1.
..
.. C (O)
Df fN1X)NS OF
Initial plas ma eoncentratkm,
lISU -
s,r.w!O.S
C_
all)' obtaintod b)' (' d r oiplKdHflll to time 7...-ro. mw'l. or J.l M. C 1:C2 Coefficiellts with units of <:(m('('I1trarjon, m ~'l.nr p M.
lI i~ht', 1 {Im~ ( ' U ll ( 't' u l r.l!illll lll .. ~'nl'tl in plasma follcJ\\ill!{ad-
milli,tralioll of an t'xt m''lL'ol'1lla r
tic .....•• mWl.llr JI\ 1. e l m)..
C Olll't'n l rd lio ll o f a IIIt·l al. llih· al
C.
Ceucentration of t1nl~ in fluitL.. 011 the ;j,~lTptiOIi ,itt·, IIlWi. o r ",\1.
\tt ·;"ly ,t.aft" d urin£: a ('(m..tamrate illt rd'l'IKlU" inf"sinll o f dnl~
C"
C.tllK't·ntrolltnll of dnl ~ in arterial
IIIWI."' J.I\t
C,
('.ou('\'ulmIKlIl of dnl~ in h lood. mWL or J.I \ 1.
CINI
CotK"t"ll lmfinlln( bound d Ol I-:: ill
blood , IIlgfL or J.I \1.
C_ ..
plas ma, IllWI..o r ~~1. C 'J
D nl g l'lIIK"t'n lratinn in c li a l)~I I (' mWl. o r J.i ~ 1.
Ic'a\i n~ d iOllp N .
(;1
CtJlK't'nl rllfiun nf inhibit or of II1t'ta bohsm. 1Il1i!. or ~ \ 1.
CI.
Tot.al clearance of J mg fmm plasma, l A ir.
CI.."
Toeal dt"ar.lIK't' o f Jmg fn)lll hlt:n.1. l A ir .
Cl ..",)
~'5is clt-anuK."'(" ba.~ 'tl Oil dmg l't"K'(·ntr.ttioo in hluu{!. LAir.
CL" II
Hepatic d(~.u-dIKT of dnag from hlnnc.L l A ir.
CI.~
Ht"taI d('llrdlK"t" o f N\·dlillillt-. Illl/min eN" l A ir.
c t.;
Dial)'5is dt'drdlK't' ba.'\t'll 011 dmg couceutrateon in pla.SIlla.. l A ir.
C/,
Clearance a\sudaftoe,l wit h Forma lion of a mt1a!J,olitto fmm a dmg.
l zhr.
c t.;
Hepatic dt'a mnn ' nf d n lg from plasm a. l A ir.
CL""
l nt riuslc ck-aranee of dm~ ill or~an of t'l im inalioll . l A Ir.
"ity o f n~llClIIs(·. mWi . o r J.I \ I. C ,\ _ .: \I.ui lllll lll anduuniunuu ulII<.'(' n C\' ~" tnutons of d rug in plasma afll' r Iht , X III doS{' n n ;td r n i llh ll' ri n~ a fi.\t'tl d o S{' al cquul dos i ll ~ inh'r· vak IIIWL or J.i \ I.
c.;
CUlll't ·ul r.lliun of t1m~ ill Ill'rill.. lll'lll l'a\i f)·, IIIWL nr J.i \ I.
C.
CmK't 'lIlmtiull o f dm~ ill plil-\IU;. al ,11';11.1)" stOlf(' during a n msla nlran- inlr.l\1:"IlCItIS infusion, mWJ. ur J.i \ 1.
C.. _
,\\l' r~{' tln lg conc eutra bcu in
pld.\lIl4/, clu ring a dosill~ i'JlN\~J al stt-....I)· slalt· 011 d(l lII i n isll' ri ll~" fi\t"d diN' a t t'{!ttal dosi ng tnn-rvals, mWJ-,. or I-I \ t.
C..._.: ~ l a'{i lll lll n and nuninuun t'(lIl(,'I1C.. _ Irdfiems of dmg ill pl.tSIIl;& af Slt';lcl)" slaft' em adminis!t'ring;& fi'{{oe,l dust' .II equ a l clus ing int e-rvals, m!ifL o r J.i \1.
C,
J) n l~ ("IJ11c't'lIlmfifn) IIl1hollllcl ill lol al hoc.I)· wate-r. mWI-- or pM.
lAir.
C.",....-
Peritoneal dialysis dC'ardlK"t'
C".......
~1 a.,i Ill U Ill a nd m inimum limits for p la.'lIIa dnl~ ("Ilnn ·n lrdfMms. 1llWI-- or J.I ~ I .
C"
Unbound dm~ (·ollll.'llfr.t tio n ill plasm a, mWJ.. or )1 ~ 1.
C k".u-d1H.,· of unbound drug. l A Ir.
CII,
Unb ound plasma (.'t)lK't'lll mlioll of illilihilllf, mWJ. or 1-1 \ 1.
CAIIK."t'nfrdholl o f ffi(1ahofil t' ill pLaSIila. '"WI. o r 1-1\1.
C,_
C.tIlK"I-utr.lIMlIl of dna,:: ill hlcMII1lIIWl. o r J.i 'l .
plasma. l A ir.
C(m)
courx-utrutjon of d nl ~ ill
JA M.
based o n dOlJl: ("II1K't'llfrdtlon in CI." CI..fl
,\ \'{ ' m~t-
111li,Ls uutshh- plasma, IIlWL o r
Cl'"
CUm ) Tot al d (';\mn("l.' of a rm-t abolitc. CI· ,.u
\ l illi u llI lI l ('1ltK't'nt r.tlin n n"Cluin'tl 10 ohtain a pn'tIt.It'nuint"l! tnten-
Renal clt".uaIK"t' of tlmg.
tAn .
\"(' llt MIS
.~
DEfWlONS Of SV.YaQlS
IJ,.
Luadi ll ~
IJ"
\ laintl'llalln ' dn"", of a f!Wtl.tlOSl' n-WlIll'll. 1Il~ o r ~ullolt"
U
v
__
dose. m~ or ~.IInClI(' .
\ t u i lllll lll mai nft-ll<.IIK,(· du!>(' 10 r-u..un- th .d tiM.' plasma dm~ con('OI'ntrat ~ >II " 'III;UII~ \..ill.in C..,.,,and C.lo ....... Ii mils tillrin ~ a (k)O; i ll~ Interval at st eatl~' ..tat e. 1Il~ or
t".
Ralio of unbound co ncent ranon in pla.\ lUiI and lotal dru~ (,(JlK,'ntranou in blood. un uni ts .
ft·,
Ralio of unbound and total sih 'S a..'iLil.r.bk fo r bint lill~ nn a pla.\IlU pron-iu, 110 units.
J"ff
Ratio of unhound and a\'('r.t~(' tl.. tal dm~ rono-ntrations in intrat, 'lIl1lar "uids , no units.
f liT
Ratio of IIllhoulltl and to tal dm ~ conccntranons in tissues (o ub idt' plasma). 110 uni ts .
y
Shapl' fact or in conce nt rat ionrt'Srx)IJ ~' n-lanonship. 110 unit s.
GfJl
Glllllwmlar fi ltration rate. 111 11 mill or l;1l1'.
k
Eliminati lln rat e constan t, hr - I.
~Illlllt"
F.
E,tr:.K1illll ratio.
IX :',II
{;onn'ulratioll ~i\i ll~ one-half tiM.' ma"iIl1ll1llI'lT('1. IIlWl. " I' ~ \ I ,
E"
IIt'pal ko l' \ l md iull rutio , TlU units.
f:,.....
\ I,l\ illllllll ('lTl'1 , uutts of re -
1111 units .
SI XlII M' uu-asureuu-ut .
P
H illa\~li bhi li ty fir d m ~. uo units.
h..1
Ratio nr I XIIIIIII til Ini al d m~ conl'Ol'lItmtilllls ill pl.eeu a. nil units .
t"
Di al"''iis cl..aram'e- as a rrd(1io n or tUlal' cleamno- dllrill~ a (Ii al~"is In'a lll MOlIl, no units.
/;
•
ka
Ahso rption rat e co nstant. hr - I. Ehnunatjon r.lIt' constan t whilt' a P"'tiMlt is undergoing tlialrsi' In-aIIlM.'nt.1Ir - I,
fi·
F ract ion of t1nl~ "'~.... te-uuc-ally ...."".liLahlt' 11Iat i", l'uTt'!l,lunt·han!:t'll in urine. lin uuits.
k"
FEV,
Forced (·xp i rdt () ~· \UllInK' in I second. I ~
k.
Frecnou or tlnl~ t'likrill~ tht' live-rtha i Ml'ilp' -s l'limi rlalioll 0 11 singlt' I'la.Ssa~l' t llnlll~h th ai o r-
kJ
"'"
~all ,
110 units.
Jm
F"rad:iull lOr IlnJ!!: sph" Illit-; J I~' ;l\'ailah lt' tha i h t'(lI\\'('r11' ! to a IIl1'l:llx,lilt'. 110 uni ts.
f ill
Fract ion or ..d min i..lt' r,,1do!>(' or dnl ~ that l'nh'f'!i ti ll' J.:t' llt' mlcirl111..-liou us a nu-tabolin-, no un its .
F
•
,
ft·
I"'
Ratio or un!'numlilut! hltal dm R ('OI K'('llt mt ioll~ in pla...ma Ulld("f' t'Uullililll\s or a1tt'n,1 bintlinR- no units.
Hatt' constant ilS-\lldatl'll wit h l1.t ' formatio n of a metabolite, 111' - 1.
/;
Inhihitio n t"fluilibrimn constan t, mWL or ~ ~1.
k (m )
Ralt' constant for th e d ilUina! ioll or a lIll'taholitl' , hr - I.
Am
M k hiU'IiS·\h ·uh 'u coust aut, mWI. o r ~\ I ,
I'm '
\ l ichal.'lis·\le ule n constant. t'Xpres sed in te rms or lot al plasma concentranon. mgIL or p \ l .
Fraction of filn-n-d and !>('(:rt'It't!
Rat io (If unl .Jl.lIltl and toral dm ~ ('OI.IK,'n t r,dion~ in plasma. no umrs .
U rillal)' escn-non rail." constant.
11f - I ,
drug reabsorbe d ill tilt" renal tu bu lc, no units.
AS\lx1ali oll co nstant for tilt' biml · i n~ of dr ug 10 prot ei n. 11 1J1olt' ,
Kp
EqUilibrium dist ribu lion rdtio or
dmg ht1\l.'t ... n tissue and hlc...1 or plasma. no umts.
k, k. )...; )-t
Fr.K1tonal rate at which dm 2
ko""'S tis~ut' , hr - I. Frat.1tomll tUITMI\"t' r r.tle , h I'- ', F.\plnt' lltial coefficit'nls, ltr - I.
OE fNllCl!"iS a S¥MaOlS
. Iv
'"
Slope of Iht' center of It... inten..i~· of n.~polIst· \"t' nus t.. ~ con('t·n l r.d ioll ('1II'H ', units of re-
'."
DumtMlII of a constant-ran- infu sio n, hr .
Tm
~ 1 a.U Ill II Ill rolle of tlm ~ t rolll~pllrt (w't.Tt1 km) into Wllm tnlmM', mwllr ,
'''' "I '
H alf-lift'. hr.
.. 1'11111 ... -.
.\lRT
\ 1t~.I11 tin"" a 1IIC.lI'..,IIt· n -skk-s ill lJ( Jl.~·.
..
1.1. :\ unilk" .. nu mbe-r.
v
:-':1111I1)1;'" o f ( 1tN-~ . no unus.
f
I'I'nnt'abili~' {'tIll·ffi dt·llt . rm/mln 0 1'
V {>"
V/ V..
ws n-m . ml Jmill (II' IAlT. Hall ' of filtm lt·lI11w fmlll ulu-ru ofiltr.tliull S}' h 'm, m l/mi n Ill' l zhr. J le-patu- blond 1l11\\' (port al vetn plus IU'p alk ark !')') , I/ m in or
lA,r.
e
Hiltin of conc eutra nou ill blnnd (, '11 10 thdt IIllhutllltl in plasma.
"-
.\ ("(.'11111111a lio l\ r,olfiu (imlt·'d . 110 uui t...
&I
Ratio o f u nhuulJ(l c k-aran o- of an
Individual patk'Il1 In that or a
~p-
•
I'
•
I'
\'"
",
1("
Itt- nat fUl K.1KIII in .III indi\iftual p;.d it·nl a.~ a fr.K1iun u f n-ual flllK.1iou in a t~'Pkal l);dit·nl. no units. It l le uf l'tlll~tani intr.l\l.'nul!S infll ~ioll , 1IlW'1r.
II,
Tu rm wer rate. 1ll~/1.r.
-'
Salt form factor.
lUI
units.
S/\
Surfaet· urea. m Z,
t
I)o sinv; lnte-rvnl. hr .
'-,
~ 1 ;l'lii Ill U Ill d ns iuv; inh'1"\1ll ln n-lII11i n " i th in (."." .... " Iltl (.'"....... limits , hr.
'_. 'J
Tillie "I which lht' h i ~ht'l>t dnlV; (11IK't·ntr.d ion occurs follu"ill~ al lmini"il r..lioll o f an extravascular cl.l'\ot' , min IIr hr. Duration of ('fTt't.1. hr.
\"ululllt' of (listrilK ltMIIl (a pp a n 'n t) based on ( l rtl~ (1l1l(1'ntm fio n ill
blood . L BlocMI volume, L, " ollllllt' (If d iah'!lall' solutio n (111· It'(1t...1 duri ng ~ helllo(lialp i.s tre-atme-nt , l ; \"Ullllllt'
o f in itial d ilution
( 'lJIIl -
partme-nt. L
\ '".
~1 d.U lll llln rate of IUt' taholi..m I,:,' all r-nzvmati call.., mediated n''''''' lion, 1I~~/hr u r ~mok~lr.
\ '( m )
\"olllnl(' of di strihlliion (ap pan'lI t) o f a Illt1 aholite 00.'\(...1011 ih pb.-una (' "K't' ufrdlkm , r,
KW M panem. IlU units . 1ft'
of ( Ii~t ri htlhon (al'lp .. n 'nl ) tlm l?; (llIK'l"ntrollitlll ill ptl~III'l. L
\"0111111('
ha.' l'll Ull
(:lI VI. r,
Blood flow, 1) lII ill CIT 1.1111'. I>i 'lly~.ah· How in Ilt·lIIullilIJ~ ...is
Turno..er time, hr.
I 'r
PIa.~lIla
\ 're
\"OIIlIlW of dial)"Satt'"ithin lilt' pC'rilulJ(·ll! cavi ty, L.
I'
•
"r
volume-, I ~
Ali"t·tlIlS " U llllll(' of illll'al,'l1nlar fluids. I ~ Pt.)'Sioll~c ..." lu ln(' Clllhic lt·
plll-'mla in ln whi(·h dm~ dtstnbli lt'S.
I ..
of di strihu tiou (appa n ,n l ) uml t'r sn-edv -sta te C't)fuliliom 1~l-'l... 1 o n ll~l~ (.'lJlK't'nlrut!on in p!;lSmOl, 1..
"•
\'I IIIIUl('
\ ' rw
."-q ut·o tls volume oulsklt· pla...ma tuto which dru ~ distrihules , I ~
\
'"
\'olulllt' o f dlSlrihulioll (aPlldn -n u
1Ja.'oC'l1 011 unbound tlnl~ C't.lIK't'UIm hull in pl,uma. L.
WHY CLINICAL PHARMACOKINETICS? T IlOSt' pat ien ts who sufli-r from chronic ailme nts SIICI. as d iaht'h' s and t"pilers), lIlay han ' to lal.:" drugs ( ' \ 1'1)' day for the res t of their li\'l'S. Al the other extreme are tho se who laJ,,(· 01 si ll~l l' duS!.' uf a tlnl)!; 10 n ·!it·\ t' a n occasional headache. 11l(' durattcn of drug therapy is Ilsu ally IM·tWI,,('U till'S(' (·xl n ·lIlt -s. 111(' mann e-r in w hid l a dmg is taken is called a d tutl /!.(· "q~j"U'II . Bot h tI\I' duration of dmg therapy and the dosage regimen depend on the t1W T· apt'utit· ohj('(1iVt's, whith lIlay 1M' t'itlll' f ti l l' cure, the mitigation. or the pn...-e nnon of t1iSt·;L~(, . Bt'('illl'>(' all d m~s ('xhihit undt'simble d T('(1 s, such a.s d ro ws iness, dryness o f the mo u th, )!;;Lstruin lt-sti n.J irritation, 1l<1\ISl.'a , and h)l x)k m ioll, succe ssful dmg therapy is "d li,,\","(1by opti mally halandllg til t' dl·~i mhl(· and tht, un des irahle- ("rTed s. To adli("\'(' opttmul tllt"r.lpy, Ilu- appn ~ui at(' "d rug o f chotec" mu st he select ed. This decision implies an accu rate d iag:uo~i ~ of tlu- disease , a knnw!('tlge of Ihe climcal state o r til(> p atient . and a s(lllml U1u le nlandi ng: of Ilw phartuaeotherapeutk- man agement of thl' disease , T hen tilt' questions How much? How ortl' n? and How long? mus t 1)(· answered. n it' qu est ion 1I0w mudl? n '<.1tgniz('s thai tlw ma gn il\l(les or the the rapeu tic and torte rt'spon St'S an' Iunct lons or tll(, doS(' gin'u. TIl(' qll('stioll Hew oft(' n? ~i7.es the importance uf time, in thai tilt' magn itude o r tilt" effect ("\'('lIluall)' declines with tinll' follo""i ng: a single dose o f drug. Till' fillest ifm lI ow long? n't"tlJ?;lli1A'S that a cos t (in term s of side l' rT('<.'ts, tCl\id l)!, ("(111l1ll1lit'S ) is incu rred with con tinuous d rug urhniui stration. In practice . the se quest ions can not 1)(' dt\lIn1't1 Imm otu- auotln-r, fo r exampk-. thl' convenience or g:h i ng a larger dn"l' k-ss fn" I I I wilily lIIay he mon- than ofTSt't hy all increased incidence of toxicity. In th(' P;l\ I, tilt' an swers to lIlany import ant tln-rapeu tlc questions were obtai ned hy trial and error . TIl(' dose , Interval between do ses. and ro ute of ad ministration wen- 5(,ll"<.1('(1. and tl.l' !lalil'llt's pn~rl'S S followed. TIle desin 'll effeceend an)' S i~IS of toxicity we re ca re fully noted. anti if nec essary. lIlt· c1osaJ?;t· rt>¢nw n w asad jush'll empirically un til an acceptah lt, hallUll"t, 1)('I\\1.'(·n ti ll' desired erred and toxici ty ""~.L~ achieved . Eve nt ually, afte r considembl!:' experinu-ntation n il ,I la~e n umbe r of patients, rt'a.~onabl l· dllsagt· rt-giIllI'1JS were l'sta blisllt'll (Tablt· I-I), hut not without some rt-gi UW llS p nxi lld ll~ excessive toxidt)' or p n J\ing ine rTl'('1 in'. \lon 'lJ\'t 'r, the alxJ\"(' em pmcal app n "ad l left lIlany ques tions ummswr-n-d. \ \1 1)' , for exam ple, doe s tet racyclin e have to be g tcc n l"\"(" )' 6 to H hou rs to I)(! t,rTt'<.1i\"f.', whill' diJ?;o\ in can he Wn' lI on ce dail)'? \\11Y IIIIISt ox)'teK;n Ix· Infused tn trave nously? \ \ 11)' is mo rphine mo re I'fTedive given int ramuscularly thall wht' n giwn orally? Furthe nn nrl', this ('1I1p irical appnJl\('h contribull's litt le , if all)t hing, towa n l estahlishing a saft" I'rTKi in' tlosagt' n-gitllell of lInolhl't (In lg. TIlal is, our hasit' unde rstand ing of dm~ h,L~ not 1)('('11 illCrl"l<;('t1. Tn 1J\·('ft-'UlIll· SIlIIIt' of ti ll' limitatiolJS o f the e llipirical app m;ldl allli to anSWl'r Slllllt' o f ti ll' fllll'stions miSt'll, it i~ fll"(1'SSllI)' to dl'k t· fnrt llt'r into tht' t"\"t'llls thai rollow d mg: ad ministmtio n. III rifm and i 'l ri t:t) studies show thai the ma~lit utll' of the rt'SpOIls(' is a fundion or the l1ml1-'ntralion o f d m g ill the fluid b
2
o f tlwrdpy . II n\"'{."\'t 'r. na n ·I)" is a d n1lo': plat.'t-d at ib silt' of adjoll. Indee-d, lIl(l\1 d m~.. a n '
goen orally, am.! }'('I
tlM:.,.· ad in
fli t" b rain, on t ill' he-art , at the II t 'U n llllllSl'u !ar jUUdHlII. or
t'!........h e re. .\ d Ol!; m u..t th e n- Iore m O\"t" fro m tilt" ..itt>of ou.llllini"lrJotion 10 the sitt" ofaction. SimultiUK'OIls1y. IK,"'"'\·...r. til t· d m g di"lrilmlt~ III all ndK'r ti....1WS i n<,JlIdi ll ~ ttN....• orga ns, nntab~' tht· lh'N ami lIl(' kidneys. that eliminate it from the IlOl. l~·. F igu fl" 1- 1 iIImt ra te-s III(' cwnts occerrtng "ftt'r a tte~· of d nl~ i!'i ar. lmilli..h- n -d or...Jly.
rate at whk·h dm~ init ially enters the bodv ('u't't'tu its rate of eliminat iun ; tilt' (1)11 ('t'nlroltions o f dru~ ill bit..;! ul hN ttssues ri M:. nftt'll ..uffidt·n tl)"hi~h 10 d icillht' dcsi n-d tht-rolpl·utic t' lTl"(:h and sometimes even to pmtlll(,(' to,ilir,'. Ew:·n tu all)". ellt' rod,' of d mg
n it'
and
r Jjmination cxl'l."l"ll, t1.~. roth' uf its eleorption. and t1lt"rt·... In-r. tilt' ('OTK'I.'ntrJ.ti(m of dnJ~ in " "til blood anti t&SIl~'S (1t'Clint"S a nd th e e fTl"(1(s ) slIlxidl'S. To administe r dm~ optilll;lll)'. therefore, knrM·I,'d!{~· is Ilt"l"!t .. l nnt o nly of t h~' 1ll 1.. .han i...ms o f d n l ~ absorption. distrihu -
non, and elimlnanon hilt a1 ~J of till' kineti cs of thl'\(' pnx"l'S<'('S. th 'll is.IJIum llllCl.lkl,U1iN . lIIall;l~I'lI1 t'llt of 1l
TIll' application o f phann'l("l.kindk principles 10 tl.l· tberupeunc
T_~
Trealmenl 01 lnf.ect>onl.
l)go>:;n
ArneIOOfO!oon 01 ~ cc-dcc fo;~
"'" "'"
0<,00<-
Ir.c:I..oon and
"--'-'
""',..,.. .....
'" """"
~e1oe1
rno.ntenonee
01 _ e po,n
250 "'9 ~ 0-8 lit I 5-2"'9 ,ntt>CJly o- 2.4 Iv. li'>e<~ 0 25-0 5 "'9 once 0 cloy o 2-.4 ..........'Ii/rr"n by
....,.,
InIrQI'nuSCuIa<
10 mg ~ ~
"'"
Nor recom....e..d.,d becocse oIleduc ed ~
tl«. 1-1 . PL..".... " "1l' '11!r·' '1I'' ' .J I hn>rh~ tli,... In il.,, 1'i"1 (.. llo... ·h .lt....
unl ,10...,. of a fil. ).n' lt tnulrullo..I·Il"lo'iI-\l' (un llul..liull. Krfof't" lilt' 1"'..1< i\ " •• -I..-d, tI ... r..I, ' ..f "''''''l>lic''' " l ' ('1 h Iha l of t' h minaliu" . Al 11,t' 1 It. tI tv... r..to"f a " I',..]; II..·..... ..firf'. tI ralr of ..Iimi ljun Mt~b 1...., ,/ .u-...''T''jr", IRr<.I/lrOIm fn .... s..ut..... R.. St";ni)""l. \'w.. Dl1rtti. E .• tMhm . A., ilml S-ch"k II U.: f'nov-n l;d'iono( ,",-,k, in
hi<....lui\...-
rD:T_bn.. lnl I . an. f"hann....1
n..-r. TOlicul.. .)'} s;~. IWl.1
o
12
24 Hours
36
46
3
CHAPTf i I
11lt" events f(l ll(J\\i n~ dnl~ admtutstration can he d i\1d("(1 in lo two pluse-s. a IJlwnlulC(Jki"l'I ic IJlww . in which ti ll' 'KljllSta blt." elements of du'l' . dusagt.' fon n . frt"'llIl'II(.')'. am i mute o f udmuu strunou are rt..lated to d nl g k-vel-Hm e rdaliollships in the hudy. and a 1"l lln lw('Ilfl y" mll k pl lfls(·. ill whidl th(· 1"ll1l('t'l1tmt iun of d nlg at tilt' sih'(S) of at.1iou is n-luted to tln- nmgn il mlt· o f lilt' (·fTt"(1(S) pmd ul"('tl (Fi~. 1- 2). Om"(·IM,,1I of these phases han' ),t't'11 dd il\('(l. a dOS;lgt· Tt-W lllt'll ca n 1)(· t!("!iig1lt't1 to a/: hi(...·e Ihe 1!It'T;lI)('utk ohy't.'t in' . I)('spi h ' tilt" grt'a h' r amount of Infonuanon req uired wi th thls upproech. it has several ad va nlag;I'S o\"('r rlu- empiric..tl app n ",l'i l. Flrs t. aml most ull\ i lJus. dis tlnction l'im ht· III;K!(' II(,t\lol't'lI ph am l'K'tl).;illdic allt l Jlll anllal't )(I~llalllit· causes of all unusual dm ~ Tt'SpOIl'l', Se<.'Olld, Il.lt.. IliL\k- concepts o f phannacokiuerics an' co m mon 10 all dmw;; illfon llalioll ~ai l\('ll uh out the plmrm au )l..i nl'l it.,. of 0I1t' linl g 1..11I ls-lp in ;lIl lici pal i n~ tilt' phann;K'tllciul.tit-s of allot lJ('r. Third. Ilnd('rstalld i n ~ tilt' plum naco k tncncs o f a dru g oftl'n expl ains till' manne r of its list·; ()('(';lsio llally snell all 1II1tlt' rstalid ing has savr-d a d nl g th at otl J('rnist' llIay h'l\1;' 1)( '('11 discank-d or lIas 'ill~t''ih'tl a more app ropriate dusa )!;l' re)!;inw n. Lastly, ).;J1(J\\111F; the pilarmal'tl).;illdil"'i I)f a dmg ititl\ tln- clinician ill anlidpiili llg th e op tima! tk)Sit~c n -W lllt'll for 0111 im ih iti llal pal ient am i in prt't:lil1in ~ what may happen when a tlOS:l)!;l' regimen is changed. ;\ llil\ ic tenet uf clinical plumuucekim-tics is th at the- magn itutk·s of hut h tht' tkosin 'tl rt''i!JlIII'>t' amuunt !()'it t,,( plals tile'
Pharmacokinetics
Pharmacodynamics
,, , ,,
~- - -- ---
Dosage Regimen
Plasma ConeenIralion
,
,,, ,
~ - - - - - - - - - - - -~
Site
at
,1_ _ Action ____ _ _
,,, ,
Effects
:, ,,
\~ - - - - - - - - - - - -~
t 'l " , 1_2 . .\ n ~ I'pr"",,'h In tI... ,I." ;!C" fir ~ .I."'"l(t. rt;(i mrn n it, phartn;K'
r,...
•
CHAYlH I
'i('n-ral IIm e's had to he
~n'll
before
d nl ~
uccunurlatkui
Wit..
sufficient
10
product- u ther-
apt'lIlit' concent ranou. Hill! the rapy 1,( '1.'11 stop pe d hefnre 111l'1l. th e dm ~ lIli ~hl have I)('(,u l holl~hl im,(ft"'l1in' ami perhaps ahandoll('(1 pn.·maturt'ly. Altt·Olillin .·'>', larxN closes lIli~hl ha n ' 11('('11 tried , (' .~. , rq~i llll'1I H. Ah holl ~h a th erapeunc rt'SPOIlM' " 11111d ha ve h"'('11 nlu ally p roduced IIl1ilt't..'t· pl;tble loxidly when a dnsill~ rate sllffid t'nlly h i~h 10 he d Tt't..1in ' at'l ltd y "'~.L~ maintained. Only afn-r its ph;tnll;IC.'t)!cillt'lks had 11t'('1I t1t>fillt'(l W lL" Ihis d nl,g Wit'(l sut't.'t..'ssfllll)"·, Q llin is t'l im inaf('(! slm"'!y am! at't..'lllllllb lt-s t>xh >nsi\,(-ly wnh n-pean-d d;uly ad mi nislration . 111t' allSV"t>r ""l'i 10 ¢ \'t> 1 1I ~t' t111'it ' S l"'l'r lilt" firol fl>w days 10 nt pid ly at"ilit'\'t> therapeutic Sll{.'t..'t,.'SS, foll"wt'(l hy small daily clo se-s 10 muintuiu ti lt' p l,L"llIa coucentratiou wn hiu thr- therapeutjc wi ndow. TI lt' plalt'au situation in Fi ~. 1.....1 shows thai ho lh IIIl' widt h of lilt' Ilw ntllt>Ulk window ami lilt' sp' 't"fl o f dm ~ elim ination gm 't'm IIIl' Si7A- of lilt" Illainl t"nann>do~ ' an d 1111' Fn-, qm>IIl'" o f administration. \ \1 lt"1I the \\; fI{!ow is uarm w and the d m ,g is diminatt"tl mpidl)·> small doses mu st 1)(> ,gh l.'!l ofkn 10 ." .'hit'n' therapeutic s m't:'t·s~ . Bo th cvclosponnc- and d i ~o'(ill lIa\'(' a narrow therapeutic \\; m lo\\', hUI hl 't:';IIISf,' t')'{:II)SIX)rillt>is e1iminatt"f!Ill11t·1I num- m pidly than d i ~()\i n . il hils to 1)(' ,gi\1.>11 mon- Frequently. O \)1odn is an ext reme exaruplc: it also h a.s a !l am JW therupe-utic winduw hil i is t,lim inalt'(l wit hin minutes . TIl(' 1I11 1~' nwans o f m!("fillatt'l)" l> llS ll ri n~ a Ilw mlx 'utic concentra tion of oX)1ocin Ihe rt'fort' is 10 illfu ~> it al a p rt'(; ~> am i cousta ut rate d in't(1 1)" into lilt' blood . 111is dt"gTt-'t· of t't llllmi is nol IXJSsih lt>\\; 111 utllt'r Illud!"s of ad mlnis tmtton. Bt·sid t>s. had oX)1odn 11t'i:'n ~\1.>11 o r ally, Ih is I x ,l~lx-p titlt> hc rmom- \\1Juld 1.01\1,' IX'i:>n dt'sl rt'~1,'(1 by tln- p mlt,(,1)"1ic (>UZ)ll1t·S in ti lt" gil'"~ tminn-stinalfhuds . ~t Olllh i ll e , ~Wll orally. is also t1t·s ln ~·t'i:l substantia lly before (>n lt-ring th e gt'lle ral circulation, hu t fo r a reuson r.;landilig pbannacoktue-ucs and coucent ranon- re"I)tlllst>n 'latin nships hilS led in n -cent )"t'il ro 10 the exit-m in> app liC'"dtioll nf sucll in fnnnal io n by tilt' ph arm m.'l>ut ieal ind us try 10 d m g dl'si~ l , Sf,>lt't.1illll, mltl d l'\"t'lopnwlll. Fo r t·xalTlple , a IXIlt-nl t"flm lxl\Il\(l fOIlIlt! to l)t> pno rly alit ! un n >liahly ahso rh('(1 and iu lem lt'1l for oml ad m inislr.\tioll llIay lit' sl1('I\1,'11 ill fa\1,lr o f a sss polt >ut hnl mort' (>xtl'll sh1.' I~· an d rdiahly ahso rl)('(1 t'tllllf'l"lllIld. Also , IImllY of tilt" hll"je p n ll1.>Sst'S l'tilltmllin,g IxlllI phannat"flkind it's alltl n,>sIXJIlst> art· sim ilar at'm ss mam malian slx't.i('S sllcll lhal dala eml II(>..>xInll x llated from animals to p n '(liI1 1Iu:lnl ilalh l.,ly tlte likely he h;t\; or in human s, T his lilian·
" ';!it. 1-3.
\ \1..." • •Im )/. i .
~ ...n
in
• 6"'11.10...· .,..1 at Fi",. 1ti nK' inlo'r, ..... 1. (.I.·,.. ot,,,1 l~' II..· .1Tl",,,l. il . .. (~lIl1l1lah ..
"ilhin 110., 1...ly "ntil
Therapeutic Failure
Regimen 8
;t
i. n ·'...~ .... I, Will, n 'Kin..·" A. 11"" "P""Ii<' " KU .... i, . -hit'\,,1 ;U,
pt 'I" " "
' 1....,)1.1, ,..ot inili.J ly. Wil h ..,;""'" H.
II..· lI"' r"I','uli<: "1>;....1;\1' i, ...-I,i,"\.,,1
''''In'
II..• pI..., ,,,,, ,In, l': " .....·" I... titll' i, t1h i n"'I" ~· " •• Itij.:h.
Therapeutic Failure Time
•
CHAPTH 1
titatiw fnllllt"'\~lrk improves rhe chance-s o f sdt't.1i n~ not only tht" most p mmi sin~ (,( 1 1ll 1)( ltl ll{ l~ h ut also tilt" corn-et nmgt· of safe doS('s to first tes t in hu man s. lncorpo ranon
clement wi th the-se t·arly Phase I stud ies, usually in he-althy su bjects, \\i th assessment of any sidt· effec t s produced. helps to define candidate d(Jsa~t· forms and rt'~i ll l('IIS for evalua ttou in Phase II studies conducted in a smal l 1I1111l!Jt'r of patie-nt s. Th e M' ph,l\(' II stud ies aft> aimed at de fining the most likely safe and e ffic-dliolls d()54I~t' rt'WnwllS for use in the subseq uent larger Phase III clinical trials, o lten i ll\ul vi ll~ ll1a n~' t1lollsalld s of patit·nts. Ultimately. some com pou nd s pmvt' to ht· of sul1k i t"llt 1)('llt'fit and safeI)-' to ht· approve-d for a particular clinical iudication hy dmg rt'gu latUfYaut hori ties. Evt-n then tilt' d m~ n ndt'~ot,S \i rtually continuous postm arkt'li ng surveillance to Iu rtlu-r n -fim- its plmnnat'tltlwnlflt·util' profile. This S('tillt' nce of events in d m g dt...-elopmen t and evu huuion is dt pil1t-d sdlt·matim lly in Fig . 1....1. FiK\lrt· 1-5 Illustrates an impo rtant problem idelltifit>
of a
phan ll a('t Jkin('ti(~
h~t'tll(' r
o
PRECLINICAL TESTING
G=v In vitro PKlPD Animal PKlPD
<::::;:7
CLI NICAL (HUMAN) TEST ING Dose (Cone) Response Trials
c;;::::J fi ~
PK-gui• •• Dose escalation
Efficacy
Safety ~ Dosage Assessment Selection
Toxicity
Population PKlPD Characteristicsin Large EfficacyTrials PKlPD in Special Populations
= =
PostMarketing Surveillance
Patient Variables
IAnimalTeSting) PhaseI
"lit. 1- " TIlt' d' '''''~ '1l11 '''llt and ",I lll.'Il1 lIlark.1illll: uf II ,Iruli:. TIll' pn ·lml1lall .lata l...Jp:.lo it"'lI lifnm"ni~! nl:, '''''''I''MIIKL, and h. '''~.'''t "'.,fu l.Ic (; If I"'hlll:, in huma ns. Pha..'S I. II. alld III or human a,""Ssnlt'ut 1:.t'1lt" r...r~· n ,m "p'nK I I" II..· 6"" ",I",iui, tr>lli.lt' I" I,,",, ;tu ri>. ... ...Juah" u I" .. 4.'11.'(1 ;1.11<1 II..• 1a1'):t4" In..ls. """I" '(1i",I~'. I'I"' nm.....l
pot'''''''',
~
25
~
20
~
15
D
"'111:, l ....s. TI,... Iai ~' .Ie...•..f ",oufan n n'(l"in'(l l" p".I".....· , imilar pn>lh rornhin Iim.'S in 2lXl ••dnll p;llUf ,ln' lI: .Ic""lll-'t·. Enr. J. elin, pham...· ....1. 9:1-'l . Il:l7S.1
o '0 10
5
o
N OJ OJ OJ OJ OJ OJ OJ Ol Ol Ol
V ~ ~ ! 1 I ~IJ:~~ Daily Dose (mg)
•
O WTUI
a~lIlalll wa rfariu Iw('(I('d tn p n l(lm."l· a sim ilar pmtlmnnhin ti mt' (an md..-x (If h1()oc:llua~. uJ.,hilily). SUlln:t'lIo of \"" riability ill d m g n "!'r_n!'iot' indmk' tilt" p"titonfs agt". ,wi~llI . t!t"P'''C' (If ol: N.'\it~' , '>1)(> alKI dt-,:n't· o f M"-'{'ri l)' o f tl.t· c.1ist·a'W ', th"'Il;dit'nl's Rt' Jwtk lIlakt'tlp. ut!K'r ( I OI ~' ("II IK' IITt'n l l " adlllinL\ll -c.l. ;,u K.! ("m; nmmt'ut al Iactors. Tl a- n";lIlt is thai a sta ndanl d dOlI{ lIla~' p rtl\'t" tberape-eric ill 'iOIIW patients. itw ff......1i\l.· ill otlH.·n . do ...agt· n ' ;IlH"1l am i tovic ill ..till or hers The Iwt....1 to adjust the (1oY.~(' «'; IIH'II of a dru~ for an indi\;pJrint>, a n illlllllll1o"iupprt"S.'\il1l1 11...... 1 ill lI~an tran"'planta tion , \\i tb tl. t"\(· t l m~ . a nti with rnan~' oebers. variahi lilY ill phannscoktre-ncs Is a majo r "iOlHU.· of total \1Iri:,hili ly in tl m~ n"'p:lI1'it·. It ... hll'l.·Ullli ll~ iIK"1l·a.\in¢y l'Ofll,nOIl to v;ain a.s 'IIIK'I. infonna tion o n va riability a'\ Ixn..ihlt· t1l1riult dm~ tk"'l.·lopllwnt l~' j:!;atht·rillJt. allJt"it lilllitt'ti. ilKIi\idual pla.'IIJd t·olK"t"lItr.lIion ;IIKI n... p:lII.... •tla ta in a t ug,' (lllJlulal it m of patit 'll t", tlllli lll't Ph;......• I I J d ini<"aJ t ria k At lt ' fIlph ;In' tllt'lI 11I.uk· til at'("tltlllt fo r th is \1lriahilil~.. ill te rms of sud, pa t....n t c hardll.1:t·risl in il.\ aV;t· .IIKI wt'i~l1 t , 11k "\( ' IJ>t.1"ulntilm l')h a n nal '01J1K-ticl pI Jdn nal"tKI).T1Clm k shKlin Iorm a Il;,l\i "i fo r tic.....,.... • n-,.,IIII·U recomna-ndatlons in di nit-a! pr.Ktic:t·, Coatllllillidmtitm of \(·n:·r.t.l dm gs til a pa twnt , pn.",a lt·n t in chuk-al prdll.1:kl.·. can IXJ!i(" p mhlt·llI"i. ,\ It l.t M I~' tht· rt"lip lllst· produced by f"'"d('" h dm~ alrnw rna>' ht · pn'tl it1:aIJlt·. that p",tIlK'(..1 I~' tilt' t'(, mhillatinn mOl>' IK' 1l"">S certai n a nd (It,(,"d.\ionall).· 1IIlpn.'tli ctilhlt·, Ketot"(IIIaJ'.ok· . (IIr t·""mpk·, d t....,)jd of iIllIllUlKlSuptln .......llt ac.1i\it)•• plllh'ntia tt'S tt. e dTt"t1: o f t;'l.,It)'l;lx ,rillt·, I't ~ sihle t'UII'it'S uf thi s lind of e !Tt"t1: art' U14U1)" , III th is in.\laIK' ·. il\ in man y o tllt'f'. ti lt' Inn-n....1:iu n iIlH'!\l."S a dw. Il~(" in phamlat-"t)!.;indit:s. SUlllt' t1 nl ~ stilllulatt" drugon
t;r
:\ h l OW, II........ ~ pL..t , p!-""" ,,( 1 ~t, lIin Irt..10 I" i' ~..... ,""It. II"" .I."U'll: r.l,' , II re- I~ ('(......I.-nhlr >...u.tion In I '''' Iwlth .... ,,;&/, (O" r m~ •• 3.Ir. ",M.1 ( Ro.. t1 n fn,m 1.", ,,1. I ~ : t:lT.",'h o( I'hrt,~t•• n in poo' h ,h WIlt. rt"I.,,,y In ~ , Itl it. .""" "('''1...1;'... 111 1'1..."", I n KI" It",.-..I . :fT 1~"( Dn'lt' I" ft,·L. I ;' >II1 In TI lI" r 11.... ".. C.. nn.. ,IM ""'" E.I,I,..II " , D ,S, I).. . ''1M .. ,,, I II , ~ C. I'rlt:l ",..I. M..... li ILu., 1 ~ ""I. IIl' ",.,j 1l"'ll1~I ,,~r. U173 . I'l" 227-2.1.>1 ,)
n it·
1-6,
'~ .......Ir-.I.... ,
•
50
• • • •••
• •• •• •
•
•
•• • ••• . • ••• :!. • •• ••• .!J•••:
·:-. Iot'." ii .~ ..... ~},.;~
•
••
••
• •
• ·1
··.Ii. .'( ~ o
5 DaI ~
10
Dose (mglkgl
15
7
1Ilt"lal x llizi ll.lt (' II7.)lJlt'S and hasn-u lim /{ loss: o t lw TS
Inhilut I ht"~· {' II7.)"Il1l·S a nti slow ('Iillli·
nation. Still others interfere with drug absorption. SUt'1l iutr-ract ious are grad ed. tht' d lilll ~t' in tht, pbe nnaco ktnencs o f 11 elm !!: va r ies ('on li llllc)IIsly \\ilh llit' ph..ma ccncenrration n f tinilltt' nK1i ng dm~ am i IIc'II('(' wil h tum -, Inde-e-d, ~n'll in slIllk-it'nlly high doe-s. almos t allY dm g cau intr-ruct with anot he r. It h al..... I) 'S it questionof dt"grt'l" Ultllt'rstamling t ilt" lilian· lilali\"{' elernents of interact ions ('I\Sl1n'S tlw more rational use of d m~ lhal may ,wl'< llo 1)(· (.,();'ltlm inish'nr-d. Fij..,1l.l rt· 1-6 illust rates a sil lml ilJll in which lI11m itl l ri ll~ of the dmg concent ration Illay ht' bt'lwfid al. Ch'N the narrow mllV;t' of tilt' daily dUSt, of tlu- autu-plleptlc drug p llt'II)1uill, fi ll' plalt·au ptt.~I1l;l t1m ~ l'C lIll't"lItmlio ll varu-s 1ll00rketlly ""i l hi n Ill(' p atient population , Yd till' tlwrspc unc ""indow of pht'n, 1oin is nar r ow. 7 to 20 IIlW[.; 1N." "I1t1 20 Illgll... tln- fn"' llIt'llt~· and the
,
Section I
ABSORPTION AND DISPOSITION KINETICS
BASIC CONS IDERATIO NS
OBJECTIVES The reooe will be able 10: Define rhe following term~: Phatmocokinelio. inkO'oU5Culor cod
ell,lroYo:Iculor odminiS ll"otion, absofphon.
drsco
sirian, distribJllOO, metabolism. excreeon. fif$l-pOSS effect. enteroheparic cycling. com-
IX"""·'"
2 , Disom the limilolionsro interpretation of phormocolinetic dota imposed by ouoys!ho! fo,1 10 diSlinguish berween cceccords odminislefed le.g. R· and 5-isomet'sl Of between drug and melabolite
3. Show the general contribution 01 moss balance concepts to drug ObSOfpliOn and drug OM melobolite disposition _
Phannacoldnencs hit.' mall)' uS{·flll llpp lk liliu llS that skill from ba., il· L'tJlll't'pts. Tht ·~ · concepts a rc dt...·t>!0IX'l! in this ~'Ct iOllllf the !XX)". 111is cha pt e r sllI:'li fieall)' dt·filws ! ('fIll S and dt' S('rillt·s a basic model for d nl~ ahso rp tiol\ and di sposition .
ANATOMIC AND PHYSIOLOGIC CONSIDERATIONS ~ 1 (';l-s u n' 1I 1('1I 1 of 11 dmg in til(' " ud)' is lilll ih'
Sites of Administralioa Then- an' several sites at wh ich d m gs an' I'(JII1 ll1tmly adminisll'n'tl . The-se- sift's lIlay 1)( , d 'ls, ifit.'tl us t'illlt'r int r ava scu lar or extravascular, t ' lt m n I.Sl1l/u ,. administratiul l n'(t' rs ftl tIlt· place ment of a drtl~ t.lin-c:tly into the hllMJfl, t·itllt'r inl 1a\'I'nlJllsly or inlm-arh'rially, Extmnl.';{'u /a,. IIlIMlps of administration indlltll' 1111' oral. sllhlillWml, buccal. int nuuuv cular, subcutaneous. dermal. pulmonary, ant i n -ct ul mull's. To enn-r Iht' hllMJf!. d m g ad 11
CHAYlH 2
BASIC CONSIOU .6.TIONS
12
m in i"II'n'(! e:dJ'
is adm inislen'(l inl ra\"\.s<:llla rly. Dm ~ llIay also hI' atl llli nish'(('(! r('Kinnall)". c.~ .. into IIIl" p le ural o r peritoneal cavi ties or intu tln- l'f:n·hmspi nill ll uid. Ik ¢ o nal mlmuustration includes iutru-artcrial injection inlo tl.e \'t'ssd l('ad ill~ to a tissur- 10 he treated. l' .~. , mu- l'olll"in i ll ~ a ( 'lUll't' nJUS tu mo r. It is 11 pon-utialnwans of ~ai ll i ll~ a sd l'l."lh "(· tllt'ra pt·ul k· advan tage. 111is ad\'allta~l' . ill comparison \\i 11l ut lll' r routes of ad m inistnllio ll. comes alMlllt by i!wn ';lsing d mg ('ll.pm urt· !oe..:Jly. wlw n ' it is lIl'('(lt'(l. a nd dt'1.·n ·ilsin ~ o r p lll(lnd np; tittle or 110 d MIlp;t· in (-'l)( ls lI n' tllm up;lu lIll til(' n-st of the IMltly. wlll'r(' i t is not wanted.
Disposition O lin ' ubsorbed. a t1m ~ is d ist rihllt t'tl to tb l' various o rgallS of tlu- IKltly, D isl rihlllioll is iullueuc......! hy how w('11 ('at'l. organ is pt' rfllS('t1 \\;111 bloo d. orgall sizt'. hilJ(li ll~ of d n l~ wi thin blood am! in tissue s, ami pl.'rnlt'ahility of liSS1U' 1llt' lllhr.ul('s. T Il(" two prtm-ipal O ~;lIl S of elimiuatiou. tln- livt'r and Il.e kidlleY". a n.' sl.t M11 sc purately in Fi ~. 2- 1, Tlu- k i d n(~ 'S a n.' III(' pri ma ry sih' for excretion of thr- dwmi t'al ly unaltered, O f III l("han ~t " l. d m~. Tlu- lin 'r is the- us ua] orgall for d m~ lIlt'tilIK,!iSIll; l.uWt'\"t 'r. ti lt' kidneys am! other n f~a ns can also play un im portant metabolic 011(" for {..-rt ain dnl j.,"S. nil' IIl('lah. oltn-s ~, Io rnu-d art' elther furt her lIlt'f ahnliZt'{1 or t'x("rt.'lt'{ l ll ndl;Ul~t'{ l . Tilt' lin'f lIlayal."" St't'n'\(' llll{'ha ll,l!;t'{l d nl~ illtn lilt' hi ll' . 111(' h lll ~s an'. or llIay be. au important route for
t·'R, 2-I . (),K" a/ N ,rilt',J fnom .IlIY of 1111' (lI;UI~ )i h'~ "f ...h"i"i,lr"I'''Il. ,Iml.! i. t' '''\1~.'tI I~' hle...I ,,, all ' ilo'" "irl ,i ll
1I,,·I ly i' K'hlllill lt ,I..• ..(i ",ill.,li ll ("f)(..Il• . Sil .""
" f ... [mi"i' I ,,,.., i'Kl " .Ie,: a , ..,1" 1)": h , 1"·" pl..·....I -..ill ' c. 111" ·1..· " ,III '111>..,I" ' II't..I ' II..."" , ,f,l ll "~' "",I ",1:"" lro: """ I "" t! 1.-...1. 11..· .Ltrk_ " ,111 li~I'I .... ,l..,". 1 li'K'"
Heart
II.., ", ,,,, """·,'n,,·,,1 "f ,In'lt in 1"Ie,. " ...I.....1i"·I).·. 11... """" ",,·,,1 "f vrr-
" i l h "m","" n'f"r I "
hle . "I .tI,,1 in
n., ..
I" ... ,,~' .Im( .".." h., f"ll.."" ..1 fru", ~i l,' uf ...l",in i. · Ir.d i" " I" " I,' " f ,·lim i" ,,'" ''''
.c •a
•b
Other Tissues
.. Site of Administration
U •
Kidney
Enterohepatic Cycle Routeof Elimination
Renal Excretion
Gut Wall
Gut Lumen
Fecal Excretion and Decomposition
Metabolism
13
dilllilliltilllt \ulalile substa nces, fo r e xample, ~a.<;{,,(JIIS anesthetics . Another pot ential route of elimination is via a motln-r 's milk. Ahhough an i llsi~ni f1 call l route of elimination ill the mot lu-r. d nl K in till' mi lk ", a~' lit, {"Il1lSU Ill('( ! in suffkit"1l1 tlua ntit}" to alTl"<.1 tilt" slIc kling infant.
CHIMICAl PURITY AND ANAL YTlC SPICIFICITY A gt'lll' ml stah'lI ll'll l 111"('(1... to lit, miltll' about th t" dll'mical pu r itj-of prescnbedmedicnes aud t ill' spt·t:ifki ly of cln-nucal 'lsSilyS. Ove r tilt' years , a major thru st of till' pharmace utical indu stry has been to produce tlll'rapt'llli e agents that art' not on ly as safe and dTt,(:t i\'t· as poss ible hut also an' well e!la rat'leri7.l.'() to ('lISure rcproducibk- qualities. n it' majority o f admtntste red drugs today art' tlwrt·fon· ('sM'llliaJly pun' materials. and coup led wit h specific analytic techniques for their det ermination in bi tJlo~ic fluids. dcfinitjve infomlalio n about their phurmacoktnetics mil 1)(· ~ai llt'tl. II 0wt' \'('r, a la~t' numbe-r of d m~ substa nces art' not si n~le c hemical e ntities bul rather uux tun-s. This particularly ap plies to ste reoi soun-rs am i protein s. TIlt' most com mon stereotsomers found tc~d lwr in medicines are optical isomers, o r compounds for which their struct ures an' mirror images: tilt' drug subs tance is usually a r acemate, a 50 :50 nuxrun- of tll(' H- and S-iSCllllt'T'S, Soim- d mg suhs ta nces contain gpOIl1t'lric Isomers . and still others. especially proll'Ins o f h i ~, molecular weight dl'ri\'t.-d from natural products or Ihmu~h fermentation , lIlay IN.' a mixture of struct urally n-lated . hut d ll' Jllieally disttnct, l'tIIllI'N IUmk Each dWIllil"a]l'ntity wit hin the dnl~ subs tance ean haw a d ifTl'n'nt pharmal'tllowe, toXil'tl]o¢ e, am! pimnnal'tlkilll'lic profile. Somethnes Iht,Sf.' dilTen'll('('s an' small ant! inl-'tmsc·cl" elltial. utlil'r tunes Ihe difTl'n'IIl-,('S l'lUi ht' therapeutically important. Fo r t'xample , dext roamphetamine (S. jso mer) is a pOle nt central nervous stimulant, when-as the R-('nan tiollwr is alm os t d t'\uiclof such activity. Desptte such differences , mall)' commonly ('mplll)'('ti clu-mtca l :L\sayS do 1IC11 d istinguish [x-twee-n stereotsome rs. Oll\iously, und er Illest· cirx-umstauces, alk mpting 10 ' lu,lIltify the various pnx'('SSf.'S anti to n-late plasma coucentrunon to respClIIM' has llIallY p roblems with no simple solutions, Notwit hstandin~ Ihest:' problems. spc.'(.i fk Informat ion about eac h chemical ellt ity should he Sf.)u ~h l whenever possihlt·, h ll·n·'L\i ll ~]Y, sten-oisonu-rs an' hei ng produced as smgle chemical t'nt itil' S, such as S-nslrcJ>·t't l in lhe ga.stroinlestinal tml1 , fm m whil·h t hl~ dt'gnulatinn pn ll!ul1s c'IIIN Iht' hoch' alld an ' ('\'t'nhtallv t'.\cn·!t'tl illllrint'. A b:tsic lesson is leanlt"(l liNe. D islinK\lish l"lll't·full)' ht'I\\'('t,u dnl~ ami IIIt·taholile(s), ~l allY lIIt'laholilt'San' of in!t'n'Sl. l'S{X'(.; a1 ly if tl.ey art' ad!\(' or toxic. Each d\{' mi(-d1 !;'util) ' lIlust lit' ("Cmsitle rt"d Sf.'par,ltt'ly for kine·tic dat a lu he nlt'anin ~flli.
CHAPTE R2
14
DIFINITIDNS " h htlu ~h the- p rnn ·s ~t·s of aleorption ami e-linunation l ift' dt·M·rip ti\'(· and their II1t·allillj.,~ an.' app an'll! at fi.....t !{hUll...-. it is n nly wit hin lilt' context of expc-rtun-n tal o h'I: I"';llio ll tha i
th"y (~UI ht· '1IIillltirit'd (Chaps. 3. 4. a lld 6). G t'llt' ral dcfiuutous of tht' P OIl"-'"St·s follow.
Absorption i I.' III(' pm<:t'SS lIy "bid l Illlt:h;IIll-tI'l! d nl~ pnM.,,'tls fru m stn- of ad lIlin isl m t io n 10 silt ' of IIW;lSlIrt'lllt'nl wi thin till" hutly. To illm l mlt· why llhscllVti ll1l is dt·61\('(1 ill Ihi'. Wot)', 11l1ls itll' r the- ,'wills dt'p itkd in Fi ~. 2-2 ;L" a t1 m~. ~\'t" ll mall)" moves fm m IIn- :0;111- o f ad m in ist rati u n tn 1111" !{t'llt" m l ci rculation. Then- a n" S(-"\'(' m l pnssih lt' s ilt's Ill' los s. {)111' sill ' is l ilt' !{'lst miute-st uml lunu-n whe n - d t'l"lllllpns il io ll lIlay oc cur. SlIp pllst·, however, that a t l m ~ sll "in'~ dt ost n l(:tiun ill IIIl' lunu-n n llly III1M' ('(lIllplt,!t,ly 1I1l't aIM,li:l.t't1by t'liZ)1 I1t'~ :lS it p;lSst'S 11J",u ~h till' me-mb ranes uf l ilt' ~,lstmill!t's l i nlll tract . One \\'lIl1ld as k. h tilt' dm ~ ahsorl wd ? E n ' n I llo ll~h lilt' d m~ k-aves lilt' ~;lst nJi n lt'st i ll al Ira ti , it would lIu t t11'1t'{,It'd in t ilt' gencml circulation. I1t'J1{1.', tln- d rug is nul absorbed sysh 'm im Ily, Taktng Ih is a r~"' I IIlt' nt (lilt' ~ II'P fu rt her. h tlu- d rug ahsnnM't ) if all of the orally atllll inistt,rt't I t1n l ~ wen- til 1l t'j);tm ld y, tln- answer \\lII llt1 IJ(' IM)sil in ' , If, how t'\1.'r, ,lS is ('(IIll IllO II , h lond or plasrna ill all arm vein is lilt' silt" of me-asun-me-u t, tlu-u. IJ(,{",III"l' nu dm g: wfJllltl lM' detec t ed. tlu- a llw, 't'r \\1Iu ll! 1M' III"gillin', IlIdt't't1. 10'S ut allY silt' p rior 10 lilt' sitt' of measurement contri butes to ;1 d l'{"rt',l'il' ill tlu- ~ystt ' lTlk' ahso rp tiou. 11\1' ~;I' lnJ i nlt'sti llal tissllt 's and ti lt' liver. in particula r. a n ' o fIt · II silt 'S o f d im ina lioll. 111t, n ''1ui n 'lllt-nl for a n orally adlllin ist l' rt "<1 d n l ~ In ll;l'S l " nJtl~h Iht,"l' liss\lt,S, p rio r 10 rt'al,:hillg: tbl' silt' o f rm-asun-nu-m . makes Ihe extent o f
AbsOIvt iull is dd il\l'il
"t'
Gut Wall
Portal
Liver
Vein To Site01 Measurement
Metabolism
Metabolism
To Feces HR. 2-2. " tlnJ~ "" " 11 a.. .....I..\, ,'rK~""'''''' ",,,"-r.J h...rri<·n ..", I " I... .. f ...., ill ih "'~ I'H'" li;d " " " 1'T,,,·,,1thlli ul: R.."o-"""..'j" ,01 "1""'1lti..,,. 1"' ." "'1'1.1,' ~ " li.. n. 10M' hll"I I', ·n''' ·''''ihl~·. "",I ""1.. in II..· "' 111" ""'11 " r I,y ""~ ........ ill tI.., ", ll w.. 11 ..,... (.,.,,, f PO'''' ..t......p li" " . H,' ",,,, -..I "f ,1",1:.... it 1"'"' .... 11In..,!:I, II.., 1M "
"j
f"rllo .', n ~ I,,<~, . ..l""'1ltit",
' 'Io...
fi,,'
1>,.".",
"
CHA.PTER2
ahsorption dcpondeut on d iminalion. T Il(' loss as d Ol ~ pa~S(·s . for the firsl time . th rull~h sites of d illlinatioll. sll(:h as tln- ~:l~t mi n lt'sti nal membranes and the liver, d ll ri n~ abso rption is knowu us Ill('jin t-IHlu t1Ji.'l1 . Absorption is nol res tricted to oral admiuistruno n . It occ urs as w.:-II follouing tnt ramus<'11Iar. slll)(:lItall('tllls, and other extra vascula r routes of ud mi uist r ation . ~Ion itori ng Intact d Ol ~ in hl(1l 1l1 or plasma olTers a IIst'flll nwan s of a..sess illg the ('ntf)' o f d m g into the syste mic circulation .
Disposition As absorption and d imillatio ll of d Ol~ art' juterrelated for pl l)'Si (ll~c ami anato mic n -aso too art' distrihutioll and elhmnanon. O nce absorbed . a d m g is delivered sim uha Il('tlllsly hy arterial hl()()(1 to all tissue s. incl lldin~ organs o f elimination. D i still~uish in ~ lx-twec-n e-huuuution and drstrthutfon llS a ('U II st' for a decluu- ill concent ration in blood o r phsma is nfh'n t1iffil11l!. lJisIXA\·ltioli is tilt" term IIS('(! to em brace both pnx'(·§.·i('S. Dispo.~it itm lIlay 1)(· defiued as all Ill(' pn x'('Sses that occur subsequent to the absorption o f a d m ~. By d t·finitioll, lIlt' l11mpu m'Ilts o f disposition art' d istrihu tion and elimination. D ist ribu tion. Distrih utio n is the pn x't"ss of rt's"ersiblt" transfe r of u d m ,; 10 .md frnm the sih' of measurement . usually Ihe blt)()(1o r plasma. An exemple is dis tri bution !Jt'h\1't'n blood ;llld musek-. Th e pa thway fo r ret urn o f d r ug 11("('1.1 not he the sann- lLS that !t'a\; lIg tln- circulation. Fur example, dm~ llIay he excreted in Ihe bill'. sto red in and rt.·lt·.l.....-d From tilt' ~all hl :l( !l lt·r . t mllS i t into tln- small intes tine, ami bt· rea bsorhl'tl int o the circulation. B, · doing so, til(' t1m~ complet es a (")"(:11', the l'tl tf'mlu1H1tk C1Jcle (S('t. Fig. 2- 1). If all tilt' dm ~ is rt'absm !J('t1 in this manner. hiliar:v sccn-ttou is not a m ute of e liminatio n: till' ()t·ling is then a component of dist ribunon. n i l' situa tion is analogo us 10 Ollt· in whic h water is plllllpl'1.l from om- n -senotr into unotln-r, only 10 drain hack into rln- origi nal n -w rvot r. Biliary v -crenon is tr uly a mu te of climmntion only 10 tilt' extent that the t1mg fails 10 lit, ft·ahsur llt'1.l. Th is Iailurt- llIay result fmm dcc omposttion in IIIl' intestine, p' xJr absorption d Jar.K1('ri stit'S, or otln-r complica tions. Uncha nged drug in hilt' thai is nei ther n -ahsorl x-d nor dt'l'(,ml)()St1.1 ill tilt' intest inal tract is t'\"("l1tllull)"excret ed in tilt' feces . E limina tio n , Elim ination is ti lt' Irreve rsible los.~ of d Ol ~ fm m tilt" site of meas urem e nt . Elimination occurs hy two p nx"l;'sS('5. excretion and meta bolism. 1':xcn1io/l is ti lt' im...ersihle Inss of d lt'lIlkall" IIl1d lltllgt"t1 d rug. •\ln aboli.'01II is tht' conwrslou of one l'ht' mit'lll ,!)("{1t·S to anothe-r. Ck,(';lsionally. rm-tabolites are conve rted hack to the drug. As with euI('mlll'pal k l.,"(:ling, Illis nu:ttllxuic illlrmml'f'nitm is a rou te of d imination only to the t·\ tt'llt Ihat rln- I1lt'l al)( llill' is excreted or oth("m;S(' im"'1:'rsih ly lost from Iht' body. SOilS,
BASIC MODEL FOR DRUG ABSORPTION AND DISPOSITION TIlt' complexiu... ~ of hu man anato my am i phrsi o10r0' "'11111d ap pt'a r 10 make it difficult, if not impo \sihll'. to 1II1)(ld !low Iht·I)(IlI)' handles a dOl ~. I't'rhaps surprisingly then, il is a simp lt· ph armlll'()I...;nt'tit· !Il()(lt,l, depil1:t'1.l in Fig. 2--3 whit'll ha~ pm \'("{1 use ful in 1Il.1II) ' applieatiolls ami is t' mplla\i7.l.'(l lhm ug!lnul IImd l of Ihis " t)(lk. ~I on' ('()mple x 1Il(IlIl'1s art:' IIt'('('ssaly 10 t!(·St:rihl· till' pha rmiK1Ikint'til-s of SO lnC dmgs. Examplt·s of sud l llltlllt·ls an'
or
..
CHAPTER2
Tln- Illudd is h..L\t "{1 U ll a mo unts o ( dnJ~ a nd nu-tabolue. lI uwt,\'(' r. t1H' amounts of dnl ~ ilm l lllt' t.thnhlt' ('l UI nlJ l~' lit, measured in urin e din'C:tl)'. '111' tnt"I IUIllMlIlf of dm/;t 11K-tal... n lil.l.'1! illdmlt... IIlt'hthnl itc'!i in , a.\ ",..J I as el inunated fro m. !II(" I..dv. nit" a UK)U1l1 in the h()d~· is mll.llly dt"lt>mlint"(! {nlln measure ment o f Iht> hlond o r ph, ;na ('U IK't ' n l ratiu lI . F~\· lilllah'~ of t lm~ ill III(" ahsurvtiull l"Olu pal1 mc'n t art" ..tso mually mad. · int lin't11y from either hle. .. I IIT urne - (Lila. DnJ ~ at d lt' aho,()rptio n sill- inC'llldc", that w hidl is IIt"'-'t"r absorbed. for ,·u-m pl.·. d nJ ~ th ai is 1I 1 I i lllah'~' de c omposed in tilt· ga.\lminh"s lirwl trolC.1 or 1m! in th e (c"(1;"S .Ifh"r oml .\lJ lIlinbt rJ.tiun . n it' mod.·' is rt·;" lil,"visuahzcd from mass haliUK't' ('(lIIsick· rdfto lls. 11 It' clu!>t" ts al'l'Ul.llllro fo r 01.1 au)' O Ut ' trme- ~: til(" molar amo un t o f suhslall(.,\' in ( ' al-ll of Ill(' ('u m pa r1nwn h : Amounlof drug 0 1
Dose ..
o ~ ,ite
Amount
+
of drug in body
Amounlof
Amount +
of drug
+
excreted
rnelobo!ile in body
Amounlof +
rnetobo! ile el iminated
11M' ma.'I.'I. haldfK'f' nf dm~ a mi related mat erial \00; 111tum- is SIM"' 11 in Fi ~. 2..... . SiJl('\' tlie SIIIII o f ti l(· 11K"''' a llMllm h of d rug in transfer anti dM'mie-
n it' n ·latiu lI'l.h ip'" (·\ p n...._
1 in (-:'1'" I am i 2 apply
lIIKIN
Role
of
2
el imination
all ti n.' llUstarK'l'S. n~anlk'Ss of
IIJI' narun- uf tilt' absorpnon and eliminatio n p nx'-~'S . 111l')' an" part in lldrly 115(·flll in dl·n ·llIpi ll ~ mon- o unplex IIl(Mk-1s for clua ntil).i ll!2: drug absorption ami deposition . Phar-"llln,1.:I Ilf1 ;c~¥ is tiM' quant ttanou of the- tune- (, )UI'1'e of a d nJ~ am i its llH'talxllilt'S in tt.(·IMKly
Drug at Absorption Site
Drug in Body
Excreted Drug
Metabolite in Body
Eliminated Metabolite
nil:. 1-.1 , ,\ ,lrull. ,. "m"II"' I.... a1 orf....I"'lo II t...h · ..."d ..Ii"'" rn .", II to. ._""....., nort ,l,..... n p" '""" .,r ...t"'''I'h''ro ~ 1 .....'tal n' ~ i....Iil. ",It. anuoo,:....t , <:t ,poort "'ilt. t n " 1""" ,10 n-pn--.__ dtffi-n.nf 10 ohrf..n.nl d "'il. c. _ ~a1.oLl..). \1t1...t..",I I"''''
, n.....·.. ....., t".· f,,,"h.... ~..t.oL .. n tn<Jt oh<...n l .... ("\("ft'f.", .
17
CHAPTER '1
100
Filt. 2-4. Till..• t~"l"" of tln1lit "' ..\ ".... ""li'.. i" ......., "f tI... mlTlp"rfn"'llh .t.o.. I" Flit 2--.1, n ..· .. rnc"lllt .~ d , '~""I rtn ll Ii ...1' 1i1.. .. 1"·n~·"I..~· 1..
/ Drug at Absorplioo Site
75
Eliminated Metabolite
~
8
/ Drug in
'0 50
Bod~
" ~
,I Excreted
u ~
~
i., .•
of,
,1c
lOIl
i"i."·
..II'
,1<
I
" •.,rl
l. In "'i' M.ilrnl,k·.
I,
DrlJ9
0-
25
o
4
8
12
16
Time (Arbitral)' Units) .uu l tilt' ck-velopment (If appn lpriah ' lIlotl.·]s In dt·S(.'ri! ll· ohservatious and p rt'1lil1 out comes in otln-r situatio ns.
STUDY PROBLEMS (Answers to Srvdy Problems ore in Appendix 11 .1 I . Defino' 1111' tenns lish ..1 in th p fi" t o" jt'('fiw at tlU' Ill;;nning uf thi s chapter. di slill~ui sh IX'h\1't'1I n· and S·i· SUIlI,'rs can I" atl lu pruhl" lIls in ti lt' interpretution uf plasma data follo\\inJ: admtntstr at iuu of a met 'llIk mixtu n-. 3. U...illJ: F iJ:s. :2-.1 aud 2- t slx'(1Ib l(' 011 how an .LSSilY thai measures tilt' ...11 111 of d m~ and illat'fin' 1Ilt'lal ll)lift, llIi ~h l inllllt'I\('(' a cc rrela tton I)('t wt't'll p!'lsma concentrauon am) tlwm p' ·lItit· n·s lxlIlsI·. .1. Follf)\\ill ~ oral ad millist ratioll of a t1 m g lalx-led with a nlditl
2. Brit·lIy sia l(' why an unalyncalmethod thai do!;'s nol
v
INTRAV ENOU S DOSE OIJlCTIVES The leader will be able 10: 1 Deline rhe meaning of holl~ife, eliminatiOn rcie ccoscot, li/$I-Older prOCMS. volume 01 dislffbutiOn. clearance. renal clearance. and f'ocllon excreed unchanged 2 Estimore the vo~ 01 holf·liIe, elimination rote ccoscot volume 01 di!>tribJtion. and clearance
from plasma Of blood ccecerecnons 01 0 drug following on intravenous dose. 3. Esllmote Ihe vo~ of half-life, eliminatiOn rOle conslon'. ond frocliOn excreted unchanged f10m ulinory excretion dolO following on inllovenous dose . .4 Estimate The value01 !he reoclclearance of a drug from conbioed plasma and Vfine dcrc. 5 Cokulole rhe concentration of drug in the plasma and the amounl 01 d".'9 in the body With lime following on inlToveoous dose. given -..alUM 101 the phormocokinehc pClfOme!ers,
:\d lll i ll i ~h'ri ll !!
a d nl ~ illtrd\1l-"C:11Iar ly ensures that 1111 of till" d OM' enters ti ll' ~l·Ilt'm.1 d R.·\!larion. Uy rapid injection . ele vated co nce ntrations of dnJJ,?; in tile hloo d can I){' promptly adl;t'\l'(1: bv infusion at a coutrolh-d ra te. a constant eoncentratton can hI.' rnalntalned. \ \ 'ith /ltl ot lw r r oute- of aduuuist ratton can blood co ncentruncn Ill.' as prolllptly am i {'mO('IIt1,. conr mlled. of tln- two illtm\';L..culur rou tes. tilt' intravenous [ t.v.) one is the most Fre-quently (omp lo}'("tl. Intra-arterial administration. which 11a_" gIl'ah'r Inherent lllanipu lat h'(' dange rs. is n ·S(·....·("(1 fur situatio ns in wh i(:h dm ~ locahza non in a spt"t-; fic o~all o r tissue is desired. T ill.' (iispos itiull charactcristlcs of a dmg lift' ch-fi ucd hy allalFjng tilt' tem po ral changes of t1mg and meta bolites in blood. plasma . am i ot.'(-d..\ ionally u rine follo\\; ng i.v. ad m tnist ra-
non. lI uw thi s infonnation is ubtaillC"tl fol h""'i ng a rapid injection of tilt" d rug for ms the IllL~is (If thi s cl.epn- r. The- rt' lIlaini ng chapte-r in this Sf.'<.1in ll d('als wi th (...-ents folloy,; ng an e xt ra\1l-<;1:1IIar tlmI.'. 111(' pliarmacokim-tic informatio n so dt'ri \'("tlfon ns a bll-..is for maki ng ra tfoual c!c"(; sic)IJs in tl ll·rap(·utks. til(" sllhj('t.1 of sllhsc'tlllt' nt se-ctions.
DISPOSITION VIEWEO FROM PLASMA St"n· m l ult't hocl.. an' t·lJlp lu)l."tl for grllphkally d ispla}i ng p llL'ma conce nt ratton- u uu- data. O m' t'(IIII IIIOII method. shown wit h t11l't lpl.)'lIill(' ill Fig. 3-1A, ts to p lot concentration again..t tilllt' nn rt':'llar (C llTIPsian) gra ph Illlpt·f. D l'pit1("t1 in th is manner, tilt' plasma {'o n('('u ! rat io n is nhst ·....·('t l to fall rap idly imm("tliat d y aft e r a 500-mg bolus. in th is <:a 'i(' [rom appm\illllltd~' 2~J to 18 IIIw'L wi thin 3n min . Th ereafte r. ti lt' ra te of t!1"(,lint' become s 11111<.'h slower. tilki ll~ almos t a nother oj 11I's bc fo n- th e ('()11('('ntriitiflil falls 50% to 9 mWl.. Anotl lt' r 111t'!I1od u f d isplay is a p lot of the sanu- dat a o n M·m iIOKdritlulli<.' f'
19
S ol il't· t il(' sha rp hn-ak at ahoul I hr wln-n tilt' plasma conce-utrut tou is ubout 16 IllWL. Bf·fon· lhi ~ tune, tilt' fall is ra pid . Then-afte r, tilt, d l 'i ...hm- is s IOWN and . Oil thi s wnulo gan thmic plot, appt,';m; 10 l'tmtilllll" lim·urly. 111t' ea rly phase is l'll llllll(m ly r..llIl'() the tlhtrl· Imtion plum· an d the latter, th e e!im;Flo titlll I,"ast'. 111is di stinct ion i.. sometimes flot clearcut . an ' <'' 1)('(1 more compk-n-ly d ist"IIS'i('(! in Chap. 19, Distrib ution Kinetics .
Distn'bution Pfluse TIlt' distrihutioll p!l;l'i(' is so ea llt'l l be cause distribution primarily dct emnnes tilt, (·arl), rapid
Elimination Phase D urilll-: till' dtstnhunon
phil~" changes in tilt' concentration o f tim )!; in plasma ft'fI("('t pri marily movement of drug within. ruther IhlUI loss from. tht' hnt ly. Howeve r, with time . di stribut ion ("fltlilih rim n of drug ill ttssuc with that in plllSJlla is t'sla1J1ish('t1 in mon- and
mon- tisslles. and t'\"t'lIhmlly, dlan,l!;t's in plasma concentrat ion rd lt"('t a proportional dJan~t' ill tlu- (UlI("('ntmtiollSof tim ,!!; in all otilN tissues and , hence . in lilt' amou nt of d mg in the IMM.I)'. D lI ri ll ~ th is propo rtionality phase tilt' IMXly ad s kin('ti('ally a.s il sill,l!;le containe r OT ('(Impartlllellt . As dt't'lillt' of tln- plasma coucentranon is 1J(J\\l due on ly 10 elimination of dOl~ {nun tilt' 111M(1)' . this phil'>t' is ofn-n called t ill' elimination pllll"l.' . E lim inati un lI a lf· Life. n it' elimination phase is d,ar.Il't('ri7.(""I IJ)· h ' 11 p
A
40 ~-
~og, >-E
30
~~ c 00
... - 20 ~
~
.-
~
}
~
c
"- .., -
0
~-
~og, >' E_ ~ -~
••
••
~ -
E ~ ~ u
8
100
~ c -
~ 2 !1 10 ..... e g
E " ~ • • • • • • • a:8
\ . .............. ...........................
~-
~u
10
0 0
2
4 Hours
6
8
0
2
4
6
8
Hours
.'1 ". 3-1. ,\, I'L"" "" "" Il~· "l r"t il " ' (If tl..~ '1"I~lli .......uh Ii" ... aft..r a 5ln-mJo: 1.\-. 1.,,1,,\ 1";'''''1i1111 into a 7O-l~ 1);lh"lIl, H, l11(' ,Lila ill" an' " "" li'rla~.~1 a' .. "'",i~'lo:"r1II""k r~ >t . S ,>t.. lhr .t .nrt .li'lnl>" tilll' p1w.,,' (I "'WI_ .. .';,5 /1 \ 1). ( \I , " Ii fi.~ 1 (" ' 111 tl..· .L.ta "f \1110"111.. .. PoO' " 111111 ( ~"w. RI .: Phanll;lll~>kin.'tK" o( i"I""""II'''' t lw.~'1,h . yll ulI·. el i", l 'II;<",l;II"" ~ ' l1...r., f.I .'\U\h "i13. 1l1i3.)
INTIlA'/ENOUS rose
20
lift' is til(' time taken for the plaxmu concentration, a.s well as tbe amount of thl' d rug in Illl' IMM ly. In fall by OIlt··half. TI lt' half·life of th eophyllilll" determined by the time taken to fall (m ill I fi to " 1Ilw'L- is 5.11 !In; ( Fig. 3- 1B). l 1lis is tilt' s am e tmu- that it lakes for the (1111{'(' n t ra t io Tl 10 fall Im m 12 10 fi IlIWL. In otln-r words, for theophylline at till" dost" ad m illish ·rt"tl. tilt' r-hnunution half-lift' is illtlt ,!lt'IIt1t'nl of lilt" a mo unt of lim p; in the hody. It follo w .., tln-nfon-, tha t k-ss dn l~ is l'Iim inah 't ! in each su('(.'t"t·d ing haIr· lift,. In itially thenare SOlllllg in Ihl' hody. AflN I half-Iif.· (5 hr ), 250 IIlg rem.un. Afh 'r :2 half-lives ( Ill hr ], 12.') lllg n-nnuu. am i after 3 lla lr· lin·s (1.'5 hr). 62 .5 lllP; remain. In pratiil,('. all the dmp; (H7%) lIIil)" I~ · n-gMd t't! as "
/1
v - Ale Volume of .. di~lribu lion
Amount in body P1a~ma d rug ccocentrcfico
Volunu- or d istrih llliOll i.. IIst·rul ill c'stimatill/{ plols ma concent ra tion when a known amo u nl or dOl ~ is ill till' IMllly or, l'()IJ\'C 'rlit.'!y, in c'stimal ill ~ lilt' dost, reqnin-d to uchicve a ~\l '1l ph\lIla e uu vntranou. Calt'u b liollllf \'C IIUlIll' or d islrilmt inn n-qui n-s that di strihutiou equilihruuu hc' adlie\l'll ht'twc'('u cln l/{ ill tis'llit'S alll! thut in ph~llla . Tilt' amount uf c lm~ in tilt' hCIl!)' is kmJ\'11 illllllt'(liall'ly afte-r un l.v. ho lus: it is the dost, admlntstr-red. Ilcl\\·t,\·l'r, d istribution t'f!lIilihrimu ha s nnt yl'1 11l'l'1I adlit'\ '/'l!, All t'stimall' is Ilt,('l lc'l! or III(' ph~Ill;l concentration tlmt wuu ld h;l\'(' n -sulted had all d rug spontaneously c1htriblllt'll int o its final volume or distri b ulioll. To dn th is, list' is madC' o r till' linear c!C'l:lillt' d ll ri n~ the t'!iminalicm plul-"l' st'('n ill till' sl' m i lo~a ri t i ll n ic plol (Fi~. 3-1B). !>C'l.'IiIU ' in plasma roncent r at ton dunng tbe diminal io ll ph a.o;t;, ca n II(' d mra<1t' rin'l! hy thl' linear t'fj1lalio n
InC _ lnqO) _h
2
wlU'rt, k is thl' J>lopC' or tlU' lillt, ill Fi/{. 3-- 18 am! C (ll ) is till' n mn' ut mtioll /lIlC' wu u lel dt'lC'nJlint , rru m this t'filialiou at ...c'm tilll(', 111t' nq.~ati\"(' s i ~ 1 aris c's Ilf'l.'UlSt' ('C lIK'C 'ntra lio n dc'(,1illc's \\ill. tilllt' , TI.t, te rm C (l l) is an t'xtrapn !llh '(l \"alm' lind is all t'stimatt' of tlU' (1 )Jl t1'lIt m!ioll wllil'h whl'll llHlltiplic'll hy th l' \"ulllllll' It'nll , \ ', al'l.'C lllllt s ro r Iht' duSt, mlm ini stt 'rt'll. i.l' .,
Do.. - V · qOj
3
In tl)(' c':\
2.
nanon phase. For esamph-, w hen tilt' 'hNt' art' 140 m,.-:; in tilt" IXKk
{'1II 11'l'n l m t iull
of th ' 'l'phyllint' in pWTJliI is 5 mWI..
VnlUlIIt" of w stribllHoll is 'il Jin"'(:t IIWClSUnc- o f tht" ('" II'nl of Ib~t rilllltjon. II ran-ly, ' It,"'· t"I1·r. corre-sponds 10 a real volu me , such as plasma \ulu nM:' (3 1.). n.t rdCt"lIula r water ( 16 L), o r total hod). wate r (42 L ). DnJ j?; tli\trilHltion ma~'lrll ' to al l)" utlt' o r a comb ination of tht- tissues and fluids o f tilt ' bud)" F urtbe rmon-, himhng 10 lissm' l'Om porwn ts rna)" till' ....:, gn-at thai tbe \'olunlt' of (Lst rilm tion is mall)" t illlt"S tht· total l...~· ..i7.t".
To appnocialt" th e dTt"(1 of ti' SUt· hindill~. ('o nsid(' r the di'!>trilmlion of 100 mg o f a {Inag in II I· L system com posed o f ....-ate-r and 10 R o f al1i\'ah'll d lan 'o al and ....iw.>n.. 9'9'1- of dm~ is lIlL'il,rbe.-d ont o the cha rcoal. \\l l('n til(" charcoal has !\t.·ttlt-cJ. lhl' roncentratson of tl n l ~ in tht· ;l(]lIt·ous pha..... would ht, I mWI..: th us, 100 L I)f tilt" a1 11lt"lK'S phasot' ....,ou ltJ hI' n "l lnin'll to lK,('CIu llt for all lIlt' dnl~ in tilt' ~ ...te-rn, a vnluun- IIIl1t'h Jtn'alN tha n that uf tilt' total 5)";h 'lII. Vohmu-s o f di..tnbunon fo r M,II"C.1 t't! dnl~" an' ..h U\\11 ill Fi ~, 3-2. nit, l'
c -qol ·.-"
4
A _ Dc». . • _ b
5
"------'-
silK'l' C ' " and C(O) , " art· tlK" illll(KlIlt in th t· IJ(JtI)' allli tbe t!tlst' ad mmlstered. n ""'I'M "l·· th't"I, ·, Equanons -I a nd 5 t'nahle the concentranon and amull nt ill tlte hod)' at ioUl" h lllf.' tn Iw.' esti mated . \ \11t'1I tlt'(..lim' in tilt' pl asma tUIt(.'('n trdholl or amount in tbe btJti)· l'Wl lit, tlt~I'M"'I1 h,· a sinJtlt' MpOlIt·ntiai n-rrn a... ~\l'1I II)' Etl s. -I anti 5 , it is sait! til ht· (1lI0IK)K'xporw ll tial. SilM.'l' ti lt· dimimll io ll half·lift· (frl2) is the time taken fo r t he ('(lIlt't' n · tration a nd th e amount in tilt' IKJti)' to fall by OI1(".lIalf, I' .~ .• fn JIII C (O) to 112 C(O), it fol1..,"""\ from Efl_-I that :
6
o r, on ill\l' rsioll
TakinR the natural Ic~aritlllll o f buth side-s, ~ Oi l«'
. 'In - In 2 - 0 .693
nh taill5 t he important relanonsbip.
0 .693
'In - -,-
7
constant k is i ll tilt· t'\ pollt'n t in F.,+ -I and <-.III II(' calculated fmm F.cl' 7. ih 1M.' ht1tt'r uncL'nttoo lJ)' ex.a.mi n i ll~ tl H' rat e a l ",nil''' the a mou nt in tilt, 1.0,1,., A , is dlan~ll~ with time. ntis is ohtaint"ll ll)' t1ifft'n'lltioltin~ 1':'1. 5. Alt"ou~ t he lIlt"a.llin~ may
22
CHAPTH J
INTRAVEf'..0U5 D05[
dA
8
di but ~i nl't ·.\ = D cl'il,' , ., - h , it (nllnw
9
Tln- term 0 11 lilt' left-hand sid e of Eel. 9 is rln- ra il' (If (:hanKe' uf lilt" amount i ll tilt" hud)'. T his is also tlU' mit' of clnninatkm o f dnt~ fm m tht· heMl)'. Pn xx-sses such as this, in which
Volume 01 Distribution
liters/70 kg
Drug
liters/Kg
50.000 Quinacrine
20.000
Chloroquine
500 200
10.000 100 5000
AmiodalOOlI
Doxorubicin
50
Onipr~mine
2000 1000 n Jt. 3-2. 11..• "'I'I>;U'O'nl ".I""". mt" "'~,kll ,Inol:' ,Ih ln h" k , ...rit~ "'itlo·I~·_
ChlOrpromwne
20
Nortriptyline
MlfIoxi
10 500
200
0'001.111
Qiltlaum
5
Verapamil Morphine Raflllidine
2
100 50
20
DiazePim EryUlromycin Phenytoin Theophylline
0.5
Ampicillin
0.2 10
tbupreten Warfarin
5
Erythropoill'1in
3
0.1 0.05
23
INaAVINOUS DOSE
CHAPTER3
Ih", r ate of rt'ac:1:iu ll is pr oportional to ti l(' amount pn-se-nt, art' known as ji n tofmler li me· The pm pmtiollality const an t is know n 1L~ Ih(·ji n'-t,,.,/f'r rate n llu to " t with dinn-nsions o f tuue - I . Bec ause I.: cha racn-nzes till' eliuuuation pnl('t'ss. it is known us t!J<> r [i mi llotil m rate n m_~t(m t . Sill(:t' ti l(" rute consta nt can also he denllt'1.l hy ft'arnUl~ n/;!; Eq. 9 to yk-ld l'_n~',~ .
k _ Ra te of elimination Amovn t in body
10
til(' eii nuuatjou rate L't mstanl lIlity sim ply 1",-' ft1!1lfll('t11ls 111(' jmctiOllfl1 m re {if dn,1!. w/JI onl!, Fo r e xample. sint't' Ih(· half·li ft· o f IIlt'uphylliJlt' is 5 hr . tile va lut' o f its e limination ranconstant is 0 .14 h r - I . II t,IIt" . lilt" sp('('1.l u f tilt' d im illati,," pm('t'Ss n f theophylline- c-an ht" dlamd eri 7...('(! ('itl wr by its half-Iif(', S hr. o r hy sa~ i ll ~ thnt tlte Fructional mil' o f r-limlnatton is C),I " (o r '4% ) o f l l l(' d Ol ~ ill III(' bo(ly p('r hour. Fruction of Do<;(' Remaining. Another view of tln- kin etics of dru~ e ln nln anou lIIay I I(~ ,::ai,wd by l''tlUnillill'::how tilt" fraction of tlu- do ">(' n' lIlai n i ll~ ill the body (NOose ) varies "'i tlJ tiun-. By (('ft,rt:'lll't.' 10 Eq . 5.
of dose A remaining in the body - Dose -
Frac tion
11
111t" [ruct ion of tiu- doS(' (('Illai ll i ll~ is. llwrt'fo ((', ~\1 '1I hy {, - lr. Sorncumcs. it is !I'w ful ln ( ':
12
re ma ining in the body -
Fracti on of dose
re ma ining in the body = I
1/ In
13
2
1/ 2 o r SOli u f tjn- doS(' remains afte r ' ha lf-lift', % n-nuuns afte-r 2 Imlf-Ii\1's. and SCJ on . Total C le a rance . Jml .lS the pa(;mlt'l('r vnl uuu- (If t1istrihulioTl is 11('('(1('1.1 10 n-lanconcentrat ion to amount ill th t' 1)(1(1)', so 111("((' is 11 Ill't't l to ha\1' a p ararm-tcr to n-late rmrce-nt m tion to rate o f dnl ~ t>l imillalioll . Cleumue- (Iotal). dt'(Jot('t1 hy CT. , is that p ro po rtionalit y f'Ki m . Tlltl s,
111l1S,
""'
", o, .." o e '''el imino tion - CL· Conce""' .,o,Ii,O,,". .
....
14
111(' uut ts o f eleanmce, like Iho ">(' o f [low, 01(( ' colunn- I)('r unit tune. Fu r example, if the d ('amn('(' \111ue is I l zhr , then al a concentratiou o f I IIlWl.. tilt' rate of dmg d illlina tiull is I JlI ~/hr . Ortlillllrily, us the- conccut renon of 11 dm ~ i1wn '11.S('S, so dot'S its mit' of dillli1I111iull ; ch-amuce rvmafn s ti l(' s ame. F r om EII- mil.' o f r-lhrnnatton :::: k . A . Sillt't, A :::: v C; From Ell. I. il follow~ that
».
Rate of e limina tion - k · V · C
C omp arison o f Eqs . 14 and 1.'5 !('lI<1 ~ 10 tlw n-lattousbi p
15
2.
CHAPTER3
Clecrc oce • k . V U sill~
16
ElJ. 16, tlu- Itolal) dl·amll(:t· of t1lt'ophyllint' is calculated to lit· -I l Air o r 67 flit /min.
So 11m! at a (11,'-\ 111<1 coucentranou nf I mJil .. t· .~ .• t jn- ra lt' of d ill1inatioll (If tht'oph)1Iillt" (mill t ill'
hO: Nly is -I
III Whr.
C learance and E lim inatio n lIa lf-life . It is mo re l "Ollll ll O Il to refer to tilt" lI a](·Ii f(· ruther than III thc elumnatton rail' cons tan t uf a t1nl ~. Hccallthut ' \12 "" 1I.69.Vk . so tha t half-lift· is n-lan-d to d t·;lr.lflc(' by: 0 .693 • Volume of distribution ,1/ 2 - """''---'-;'C''''::''' ==== Clearance
17
Equation 17 is p Ulvosd y arr.Ul ~t '(l in Iln- abo\'(' 1lI,U1Ilt'f to stn-ss th ;11 hillf·)if(' {and d illli· mlli on ra il' constant } rt'llt'(1s rat her than contro l.. \, IIUIIlI' of d islrihut inn ami cleara nce. two ill(l" I)I:II(I"nl pammdt·rs. To show lilt' app lil'< llioll o f Eq. 17, l111lsidt' r the lise of creatinine, a product of ruusch- cnrubohsm. as a marker of n-nal fum-non. C n 'alln!IIt' !la\ 11 clearance of -:.2 1)111" am i is t-n 'nly , listrillllh>il t hmll~hullll h,' 42 L o f total hudy water. As t'X))('(.'tt>i1 hy calculatlon m inl-t E' I. 17, its half-Iif,' is .. h r. Inulin, a pn lysal'd mrid,' also 1I.\t"t1 to a\M'SS n-nal fUlld inll, has lilt"sault' t.,lt·;lr.1IIt.1' ;\-\ creatinine, I!OWt"\'N , inu lin hlL\ a half·lift· of nu ly 1.5 lrr !1(>i';lIh" il is n...tri(1,'(1 to Ih,' )6 L u f exlm' 1'Iluiar wa ter. C lt.· arance. Arc" . a n d Volum" o f Distrihution. 11l11s far , cleurunce has )1('('11 ..-slimalt,) Fnnn !lalf· life alltl volunn- of d isiri butiu li. Clearaue - can he better t'slilllaftotl iu OilillthN way. H)' n'arr.U1¢ n~ Eq. l-t. it lV,lII be seen th at d \l rill~ a small interva l of time, tit, Am ount elim inated in interval dt _ Clearance ' C · d,
18
whe-n- tln- product C ' tit is tilt, l, )m'sl)( md i n~ small an-a under the plasma co ncentrattonlim!' t-urve-. For r-xuu ph-, if the- d,'amllt" of II , I m~ is I l z min and lilt' lIn';t IIl1d r-r IIIl' l'll r.,' 1)(,t\\"' '('11 flO and 6 1 mill h I 1ll ~-m i l\/ l ~ tlu-n tht, a mo unt Ilf d Olg r-lhnlnat cd ill th ill mhnnv is I m ~. 11w lulal amount of d Olg ('n 'lIll1a11y ('lim ina l('(I, wllid l for an i.v . bolus ("(Iuals the do \(' atllllinisl...n-d. is ;l\st'ssc'(l hy m ld ill~ "p 111" inftogmtillg tlu- alllllllnh ,'!illlina!t'() in each finu- Interval, Fnun limt' 7.t'm 10 infinite tim..., and therefore.
Dose - Cl ' AUC
19
when- A L'C is li lt' lolal a n-a und er th r- concenr rutton- unu- curve. 11111s, mu-e AVe is KIUJ\\ 11 (Ap!)('mlix I·A1, clearance is rt';ulily ralculated . ;-';u!t' th ai IlwIT' is lUI needto \..110\\' til,' half· lif,' or vnlunn of t1ist rih ulilln 10 calcnlan- clearance. Furthermore, th is l,;,!t"ulatillll of d ear unce is imlt'!w lltlt'lIt o f the shape' o f lilt' coucentranou-tinu- pmfil(-. Ti ll' rdatillllsiJip !K'I\\'t'('n are-a lind ehmluntiou ran II(' applied al auy linw fll!lo\\i ng d mg mllllinisimiion , as Illust r ated in Fig. 3-.1. Thus , IIm llipl)illl-t tilt' an-a up 10 a giwn rinu-, [A L'e (f), t JI hy dt'amlll1' ~\'t's lilt' amount of , Inag that has 11('('11 ...hnunan-d up to that lillit'. :\l lt'mati\"...Iy, wlu-u lilt' area is ('xp n 'ssc'll a~ a fr.tt1iull of II.... tnt al AVe . IIIit' o!'taillS 111(' fral'tion o f tlw d oS(' d imina lt'll. :\ml th... fr.it"tion of til(' Inial art'il hl')uud a g1wn lilll(' is a 1ll, 'a.~lI n' IIf tilt" fmt1 inn o f dllst, n 'lIIain ing In l)t, ,'!illlill;llt'(l. Fllr t·X;llllp lt·, in tilt' eoL'it- uf tll' 'l)pllyllillt'. hy ,1.6 11 1" tile an'a is 4U% of lilt' tul al AVe , allt l lll:'lIl't" 4O'.t, o f th ... mlmillistt.·f('(l 5()()-lllg lIost,. or 2()O mg. h;l~ 11('('11 ...Jiminalt'll fn uu Iht'! I(KI)'; 3lXl mg ha~ )'('t 10 ht, t'lim illah 'l l. \ 'nl ulIl,' o f d islri lm lio ll { \1 is IIst'() 10 n '!alt' p t l\lII;1 l1ml'('llt mlioll to amoull I of dmg in Iht, IItKly d uring Iht, dilllillalio ll pha-"" , of"'''11 111(' \, ,JIl" obtail l(,(! by ,'xtr.tpolalioll (1': '1' 3 )
CHAPTE ~
3
INTRA-Vi NOUS
oose
2'
is a rt"L\(mahlt, t'slinm!l' of this \u11l1l1l' tcnn. Ot't'l.LSiOmllh·. when t'slt'lIsin' r-lunmntkm occurs in tln- dislrihlltillll ph'N" it is not . The lM."st 1I1("IIIoc1 of t'ak'lIlatin~ \1IIUIII(' of distrihutlou is to d h id(· d l'anllll,(' bv r-lunmauon run- con stant
v .Cl . Dose 1 AUC ·l
20
Unhke extrapolation, this method of t'stilll atill ~ \ ' is not restrit1t... l m the l.v. bolus situation hilt l',1Il hc' usc... 1unde-r a \'ari dy of conditions, t' . ~. , long-tt"nn i.v. infusions . Cm lsc'C!IU'n tly, lilt' valuc' of \ ', t·stimafe... 1 n sill~ Eel' 20. is app!it...1throughout th ... n-nuunder of thi s hook, alt holl)!;h olhl'r voluuu- n-nus are t·x.ullint't! in Chap. 19 . Distrihution Kiuet k-s.
RlNAl ClEARANCE Elilll ina!iull
CI('(· U ""
hy n-nal excn-t ion ,md extmn-nal piltl l\\1I)'S, n.sllally IWpiltit: IJlt'lall(llism .
~(JI onl., · is n-nal r-xcn-non an important route of t'limillalioll for lIIany d m gs, bul IIsc'ful
p llanllal'llkil1t'l k iuformutiou run iJ,t' ohtaillt'tl [roru analysis o f urinarv dat a. C""lllml lo this analysis is lilt' t'l)JIl'!.'pl (If ",.,IIlJ f'!nlnlmY' . "\ l1 a l0l-~lI ll s 10 to lal <'I t·arall('!.'. n-ual d t'a nlllt1.' (CI. R ) is d l'fill(...1 as th(' proportiouahty n-nu l)('t"'I"1I urinarv excn-rion rate- ami plasma l'Ulll'('lIlmliull:
bcretion role • Cl// . C
21
lh-na l d t'a nllll'l', lilt· total dl·ar'U1l't·, h,ls nnits of flow. usually m illilil(·rs!lIlinnlt· or hn-rs/ hour. Pnldil'al pnJb le'ms ari se, howt'\"t'r. ill t's timalill)!; renal d t';tf"d llt'l'. Urine- is l u llt-c1l't! cvt-r a finite IX'n od , I· . ~ .• -I hr. t1l1rin~ wllk-II tilt' plasma conce ntration is dmll~lI~ l'o lilinllu llsly. SI.(lrtt ·lI ilJ~ II.t· (u llt'1.1iI1ll pt 'rind reduces tln- dmll~l' ill. Jl1;l~ma coucentr anou h' ll iu(·n·, tst·s till' IIIlt't·rtainly in tln- t'Stimat e u f excre-tion mit, o\\ill~ 10 incomplete hladdt' r t·lIlpl)ill ~. Tlus is l·sl)(-c·ially trm- fur urine- (u l1t'l1in rl inn-rcals of Il'SS thau (,') min . 1 ,(' lIhrt l lt' n i ll~ tilt'
t'l ~. 3-1.
I,LL, ,,,;c
A
li".·;O]" pi". "r,.... sa,,,,'
(~ "K ~·"lr..' k"H jl!"·
,LoI;c rfl r 'I"'0 l'''~ lt i ll'' ..s .lhl'l..~ .·c1 ill t"i" . :J-I,'l. n it·......" lip In 3 6 Itr i . 411'. "i tl..• ,"• ..I .U·C i,.. lin alilll: IlwI 411'. of II.., .Ie · "'lmini...·rt..1 ha.' 1" '1'11 .·1i1rlin;ct
I I ~' 1I,, ·n .
n ..· ;crt·;( 1 "~lJ'MI
.1.6 hr rtllrt... ·nh ,I..· fill'l- or ""Imin. i'lI .r"I II....'1II,~·Il; , ... n·,,,;cininj( In I ...
,·li", ;n;cl<..1
o
2
4 Hours
6
8
2.
C HAJ'T E ~
3
collection inte-rval, 10 avoid t ilt" problem of iuce mpk-n- t·lll pl~;lI g . rt'(juin's II II1 fl(lifit '(! ap p reach for tht' estimat ion of renal clearance. 111is app roach is analogous In th at tak('n with to lal clearau ce-. By rt"arrdnJ.,tj ll~ F.A!. 2 1, duri ng a \"t'f)' small int erval of Ii me, tlt.. Amount excreted '" CLI/ . C .. df
22
when' C . (Jt is the l,(JlTt-'sp:m
'lee,'
Amoun t excre ted , in .: CLI/ " ( A ' t
co
Of\ In
efV(]
uc
lth In l mle rvo I)
WI
23
Th e p roblem in ca I('ulalill~ n-nal dt'am.I1(1.' then-Ion - n -sts with t's l ill1 atiu~ tilt, AUe withi n ti lt' ti nlt' int erval ( St"t' Appt'mli \ I-A ). TIlt' a\·I'rl.l~t' plasma drug conceutratfon du ri n ~ the (1.1Ilt'('!ion interval is !-?WII by «AUC wit hin inlt'mt! )lN ). 111is awmgt' plasm a (1.)II{1.'IItration is neit he r the value at tln- ht' w nnill g nor at tht, t' nd o f Ill(' (d lt"('!ion tum- hut at some inlenl\('tl iat e po int. By asslllllillR that IIII' p h SlIli' rmu-eut rution dl;lllgt'S lillearly with time , ti l l' ap p mpriatl' concenrranon is that at tht, midpo int of the (d ll'('!iull interval . Ix" cause the plasma conce ntra non of drug is in faet dlan!-?Ilg t'Xpo lll'lltially with titue, thi s assumption of linear change is reasonable oll l~' when los.s d uring tilt' tnn-rvnl ts small. In practice, til(' Int erval sho uld ht, lt,ss than an elim ina tion hal f-lift' . EXlt'liding E(I. 23 11\ " 1' all t tn«- Intervnls, [rruu zem to infin ity, 1I1ll' obnuns tilt' useful
relationship ,
ena c ecro nce "
Total a mount excreled unchang ed
AUC
24
when- AUe is the total area 1I11dl'r tilt' rl.lsma t!rtl g concentratiou- ttuu- ('U I'\'(' , T o apply Eq. 24, can - mu st hi' taken to eusu re thut allurine is colh-cn-d an d for a su ffidt 'u t ('Jt'rind of tilllt' til gain a ROIIlI es timale of tilt' total amount excrcn-d u nd langt'tl. In pruet ice, the pe-riod of tune 1I111s1 1)(' at lt'il-st 5 to 6 elimination half·li n 's of tilt' d m~ (st'(· Appt·nd ix I- B), 1111I"', if the Ilal f·lift" of it drug b in till' unlt'r of it fl:'\\' hOlln. , IlIJ p ract ical t1ifTk ·ultit·... t'xb l in t' mllri n ~ urine collections taken 11\ '('1' an at!t'(lllah ope-riod of tum-, St·\'('rt' t1iffit'ulti l'S wi th {1.lInp li'lI\l't, in unli t' collect km occu r. however. for d ru w; such ,l\ plwllolml'hil,(1 with ;l half· Iifl' of abo ut a week, si ll{"t' all uri ne formed on'T a I)('rillli uf at 1I',l\ 1 1 mon th must lxcollec t ed.
DISPOSITION VIEWED FROM URINE ONLY Lac ]; o f sll ffidt~n t l)' sensitive ilnal)tic tec hniques cau and prt '\illllsly has prewu n-dme.eurement o f the- couceutrauon of lIIall)" d m gs in plasma. In tln- ahst' lIl't' o f plasma tueusu rements. neuber \ UIIIIlI(' of dist rtlmttou nor d ('amn('(' can 1)(' d('It'nnillt'll. :'\om-tln-le-ss. useful tnformanon can still ht, ohlailJ('(l Irom u rine data alone, wllt'n sud l i.~ 1ll '("t' SSiU) ·.
TI lt' dilllinalioll half·li ft" o f lilt' ft'\1.'rsihlt, l'!IOIiIlt'sh' r.lSto inhi bitor, galallihamil u', l"itll I., l'slimah't l fmlll Urillt' data. TIlt' apprtliK'h is to plot ti lt' an'mgt' t'w n' lilm mit' agaillSt the midpoi nt of tilt' (,(lllt'('!ioll tim e Sl' lll i l(~a ri t h Illi<.'lilly and . fmill t11(' slope o f t lit' stl'ili~h t Iilit' ,
(!-\APTER 3
INTRAVE NOUS DOSE:
27
obtain an es timate o f till' half-lift" I ll t ll i livt'1~·, tilt" approach is ('asy to see. Assullling that renal d t'a r.Ull't' is constant . lilt, uri nal) ' excret ion rate is proportional to p lasm a con ce ntra non, and pl ott in~ uri nal)' excre tion rate a~.tillS t tune is likt" plotting plasma eoncent runon a~aill s t ttnu-. TIll' half-life is then taken as the time for the urinaryexcretion rate (or plasma l'(Jm't·lltr.ltio n) to fall by ollt··halr. For ~aJant ham iJw this is approximatt'1y 6 hr in a ht·alt hy subject ( Fi ~, ,~ ) , COII,·t'~' ly . wlu-n a st r.ti ~h t lille is obtaillt'(l h)' plotting the urin al) ' ewreuou run - a~ain s t tlu- mid poi nt tune , l'tlllsta nl'" o f renal clearance is Inferred. '111e 11('('(1 for using midpoint tune follows fm m the previous diSl1lssiou; the measured u rinary excrclion r ate n -fh-cts till' ;l\·l'r.l~{, p lasma conce ntration duri ng; the collect ion inte rval. Formal pmo f uf till' fu rt'going diSl11ssion is !'in'n ill Appendu I- B,
Renal Excretion as a Fraction of Total Elimination :\n impo rtant phan nal'(,killt'lit., paranlt'tl'l"is tln- fract ion of the amount enter mg the V;t' ne rdl cm-ulunon that is exc reted U1ll'haug('(l.fi', II is a quantitative measure of the cont rihntion of renal I·XI'n·tinn to (lw r:lll dmg eltm tnatron. KIltJ\\ing f e ajds in t'stablishing uppmpriatrlIlod ifil'atiolis in tIL(' IIsual dusa~(' rl";u\('n u f a d n lg for pa th-uts with \1u) i n,l1; degn "t's o f reuul fUl1(1ioll, AIIlUll ~ d m~s , tilt' value offi ' mn gt's het\' 't't'u 0 and l.O. \\l w ll the \ 11111l' is low, excretion is a minor path\\N .lYof dmg ehnunauon. Ol"l-d-sionaJly. n-nal excre-tion is the on ly rout e of eliminat ion , in whic h l'a<;t' the value o f fe is 1.0. By ddinition the difT('f'('lIl't', I - ft'. is 1111' fract ion (If II\(' amount (' n t(' ri n ~ the o rr-Illation that is elhnlnan-d hy extra re nal mecluuustus. usually me-tabolism . :\n ('st ima tl' offi· is most readily ohtalm-d [rom cumulative urinal)' excretion data Iol1 U\\i n~ i.v. admintstrutkm, since by defiuitlou. Totcl d,ug
Ie _ excreted unchanged
25
Do.. In pract ice, ca n- should
alw;I~-s
lx- ta ken to ens ure complete urinal)' rt"t,,(J\'('l) ' (i.e., collect
.'R,dn3--1,nn i/: ";ot.·h ,..
1000
,~.f'aI;:t"
u rin.' ,og:n 't;on {·UII."'1ion m1"''''''/ afl.. r lU' 1,\'. I• .tll. J. of 10 ml/:of1/:;cl.."Ih>imi l"'lt> .. I lth~, subj ..d . (R..,lr,,"'·n rm m 8i .·~ ..I, U., n ,,"n....'. T .. W,'h" T, W.. n..-Iwr, J .... 801("' no, R., S ilT. ),1.. ..,,,1 11:....,il7., II . I'han ll... ulj",,'t~ or ~;u" Ih;omi...· in I"",,,. ns ..n
f:
100
-"
~ a:
10
~
Unlit'
Ph..rm",'ol . TI,,' r .. 1Y91.1
"
;u; w"
I
0.1 0
12
24
36 Hours
48
60
72
,S fl : 4 :W- 4 2~,
2.
OW1H3
\II;m' fllr 011 It'll" 5 t'limillatiull h;Jf-liv('s), I" lilt' (~lW of ~al all t hillll il lt',fi' is app m"imah.ly 0 .2.'5 in sllhjt"t1s with normal n-ual Imu-t ion . AI any inslanL t llt' fr..u:lioTlfi' Illay II(' d l,fjl\("tl ilS th e fatiu o f Illl' rate (If ewn-tion til till' mil' of elim inatio n. 11: 0 16 of excretion
26
I!:ole of elimination Appmpriatt>l~· s ll "st it ll!ill~ (or IU.IIIN ato r am i ch-nouuuator ill
Eq . 26 , it is Sl."t'll that
27
Thus. fi· liMy "lSI , II(' t!,·fillt't ! llmi l'sti lllah·d ,lS tll(' mi lO ()f n-nal am i total
dt 'ar.tlll '(' s . l'lis is pa rtit'ulany useful in Il lOSl' situation s in whit-Ii totul u n l it' l '(IIII't:IiOIl is lint po ssihlt·. III p r act ice, estimates of e l . and CJ.x ;In.' u h tililll't i di n -ctly, w!lt' n ';"->; ex t run-ual t..lt";tr;llil't' is dt 'h ' n uilll'l! hy d ilTl'T('!It't·. 11 111s, extran-nal dear-lIlt't' is ( I - Je) . CI..
ESTIMATION OF PHARMACOKINETIC PARAMETERS To apprr-cian- how lilt' p hann
,.We 3-001 .
Pl._ .IMI UrI_ ..... 0W-1...4 ••II.wI.., •• I.. . . .1• • 0._ TI1MMEM C# Dolo'' '
08Sf N AOClN
1'\.A.S.Y.A (),Io.' '''
lJRf",((),Io.'''' TWf 1NTf1V"I
..,..... I
3 5 7 10 18
CO
"'roN
o ccec
' 2'1.13 '0" ''''(}-2 ~,
2-4
010 0 43 0 20 0 0 25
, -<>
.>-8 8- 12 12- 2.1
"""" o ... "" 120 180
BO
340 178 ' 50
CCN:f:NTU ,~ '"
'NO.N
="",,,,0
"VCWlT~
""" N " "
Im ....Tf lll,'A!. ("'\J"/ll
"'''' 133 50 63 10 18 2
" (tfIl D
C UYU./l 11VI
N"" ....J!NA!.
~""-'" H C91flO
...
'
' 00 226 14 0
'6 0 00 56
0 66 0 80 0 43
34
32
"
...
160 250 30 6 34 0 372 391
Plasma Data Alone A p lot o( p!;Lsma concentranon versus lime illdi("lill' s that IIII' \·alll('s an- dmppin~ p n ~n's sin,l)", hilt o nly a(h'r tln- da ta an' ploltt'( l S<' lIIi l()~ari tl ll n it."lllly (Fi ~ . 3-.5 ) 1·1111 til(' !tal(· li(t' and elimination r.lt(' constant 1M.' n-adtl v de!t'rmilll,(1. 111<' Ital (-li( ', 1;I)(('1l a\ Ill(' tiul(' (or til(' l'lIl('('n lr.tt ion to fall in hal( ( '.~.' from I .U to U.S 1lI""'1. ( I f U.2 to U. I mwL), is 2.S hr . so that k is 0.25 Ilf - I. Clear-lII('(' is t1t'lt-n nillt'(l by t1 i\itli n~ doS!:' hy AL'C. 111(' Intal.U : C , esli llllt1I,(!lIsi n~ Ihe trapczoldal m il' (Appe nd ix I- A), is 10.2 1Il ~.ll r/L and wlu-n di\itlt'(! into the dos<' \idds a value of 4 .9 lA ir for clennme-. \ 'olulIlI' of distrihutiou. ,'sl im a!('(1 From CU I. (E:I. 20) , is Ihe n -(on' 19 .6 L. Tht s value is \irtll;lll)" id, 'utiedllo Ihal calouluted hy ((hi d iug duS(' h)" till' Intercept l'tJ!l('('utmtin lJat IA'n l ti llle. !M.'(.'allw no t1i \t ill('1 tlislrilJ1tlitlll phase is appa n 'ut.
Plasma and Urine Data Bntlt p (,L'ima anduri ue data an' n 't illirt't! tn ('slimalt' rennl dl',mUl(" . T his pamnlt'h'r can I" , nIJl:lim'(! {rom tilt' sln j'" of a plnl o( Ihl' amoun t e-xcreted \\il ltin a " 11l('(1inu interval
CHAPTH 3
INT RAVE NOUS DOSE
a~aill \t ..\ L'C within tilt' sann- tim!' i llft·...... 11 (Fig:, 3--fi), TIl(' \t r.ug:ht Iiiit' implit'S thai n-nal dt·ar.lll('t· i\ con stan t and illtlt'pt'ndpllt (If plasma concentration . TIlt" stolx>o f tilt>liue indican-s that tilt' n-nal d t'ilr.U1{,(· of thi s dOl ~ is -I IJhr, ES.\I."lItialty the sann- \lllllt' is o!Jt
Urine Data Alone TIlt" elimination Ilalf.lift>of tilt' dOl~ (';1Il ht· ohtatncd from either excretion mit' or latin' cxcn-t ton data. TI lt' app r opriate nu-thods an ' dt'all wi th in Aplx'llflix I -H,
3.0 2.0
....§.z: ~
H It, :J.-..5·
<'1 1111 11-
St,,,,il"Kantlullit' r~>t u(I Il. , rt.....ltlat" " .
n '"lralilM,· li n M· , Lola
Ki'n , in TaM" .1-- 1.
1.0 0.5
g
e c 0.2 ~
y
~
0
u 0 0
C5
0.1 0.05
~
E
~
0.02
" 0.01
c,
0
8
4
12
16
20
Hours
HK .3-4>. n... an MM",1 f"un 1... 1i. ,liW<1h· r" '1M.Ifl i1Moal In fiM' ,-\l 'e: ""·.... un.. l " "'f"T 11M' ""'M' tulJ..-c1i<M' in l....\;a] . 1"" ,,;
o
1
2
3
Area Under Curve Within Sampling Interval (mg-hrlll
4
30
lNn AVfNOUS DOSE
Cl-W"TE fl J
A Question 01 Predsioa Had vnu , tilt, re-ader, p lolh-d li lt' sa m,' data and eak u lalt'( I III,' phurmacokine-nc parunu-ters, ~' lll lIIay ha\"l' ohtaillt"tl a nswers that d ilTN Irom t!loS{' ~\"l·11. Thi s is 1101 unusual and " i ll
U('(1Ir in llIa llY case-s when }llll
dWl"k }llu r uu swers 10 l ilt" problems a l tilt, ('11(1 o f ('adl
l"h
of a Iilli' th mll!-:h data. aflN 111(')" ha\'(' lx-en plolh'd. alld in roll lldi ll~-Orr numbers . In addition . all 1IlI' ;LSUrt'II\I' UIs han' errors lLs s.od a l l't ! \\i th all al~ t ie methods. t l lTlllitium (If , t(J"'~I' . ;ull l l l;U1d li ll ~ of ....mpk-s prior to iUla l}1iis . :\l sc ), 11ilt! tilt' sl udy ju st ('o llSidl'I't '( I IJ("('1I rl'pt'ah '1) suh">("(llIl'ntly ;n the "lllll l' indtvtduul, tilt' ,",limah'1,l half-lift' ilia)· haw ht'f 'n :U hr instr-ud of 2.S hr. For almust all d illiC'lll situatiolls. IIIis t1t-grt·'t· of illinum li\i tlual variat ion is
¢ \l'!1 to ! \\11 or 11 10"" Sij.,'11ifica nl p lace s. III this chupte r. mall Y s~lu hols an- ck-Hned. ll\ it is the firsl tune tlmt ti lt')"an- 1I ~,,(1. 11 1t'~' s)1llho l\ a n - rt' u ~'t l ft>pt ·aft'tll)· I llft lll~hoU I Ilu- hook. To
Measurement Fluid So far, lilt' phartuacokinetk-s of tilt' t1 m~ wi thin Iht, INltl,. han ' lx-eu t1t'fillt'(l \\id l n 'f('n'II('(' 10 d m !!: ill p l;l\llla. SUlIll'l illll'S tlu' fl.'ft,rt'lIt'(' is t1nJ~ ill serum Of wholt' blo od. TIlt' majuf d aTt' f('II('t' " t'IWt'('1I p l'l-sm
Use of Computers Tt ltla)' (um putt'r.- an.' \ISl'lllo all'IIF.t' p IJilnll1lt.'t,killt't i<' data alltl makt' prt'C.lidin ns. B,N .'l1 upnn slalistit'lll ('rilt' ria, Ihe.' pharma('tlki lll.'fit' l'ardlllt'It'r \·alm' s art' adjllslt'( l lo J:i\'t' llw I~'st fil of Ih(' appmpri;lft' t'(lllalion 10 Iht' ('.\ I)('rinlt' lltal da ta . 11lis appmad l 1101 (111)' pnJ\itl(,s the IN'sl t'\limalt' of Ilitf1l11wlt 'r.; b ut also in('f(';lst'S Out··... l'tlllfidt'!l<-"C ill t1lt'IIl. Alstl, appli('atioll of tilt' ~I m(' t'o lllp ult 'r p n J!.,'T;ulI fl.'sn lts in tll(' Sll lllt' all\"\o\"(' r.; inclt'pt 'llllt'1I1 of Ihe 0lwflit uf. This ('flllsistc'Il('''' (Mdllllnt h(' ad lit'\ '('t l h)' fitlill~ ~rdphi<-,
"
C HAP1f ~3
t'l!u atinm; that cannot ht· hm-anzed. 111('11, ohta inillg a lx-st fit hy 1')'(' 11l"<.'Olllto:; \i rt ilall~' impm sihll' , 11lis limitatiuu does 1I0t ari se lISin~ a compute r: any equa tion can Ill' filtt 'l! di rt"<.-tly In thl' 1'\I)('rill ]('lIlal datil. Xoucthek-ss. a ~n'ul d eal aillmi (Lila is lea rned by di spla~ ill g " W ill gm phil'ally, 0 11(' gains a f('t·ling for tln- quality o f the dat a and thl' ('(!lIation that is I11l l' 1 lil.t>ly til dt'S('ril ll' them app ropriatdy, 111l' pa mTllt' IN \11111t'S nhtailwd by t')'t· also gt·'ll'r.tlly M'r\l' ;L~ su itabl t· slarting \'1III1(' s in a l'lJlIIputer pm~rmn. Because of IIIl' ~n'al 11l'llt' fih lu I( 'an l ill~ ph anllaml.int't il'S gaillt'l! by plntling data, tht s r-h-ment is Inco rpo rated inl n lIl 'Ul~· p r obh-ms thnmglumt tln- book.
IFIICT OF 0051 An adj m tnlt' 1l1 in dOM' is ofh-n 1\t'('(' sSilry to achil' \'l' optimal d m g therapy. :\ dj llsl lllt'nt is mad t, mon- n 'ud i l~' when tilt' \·alllt·s of tilt' plllln mu.'likillt·tit, p'lr.l.Il1l'h ·1'!i u f a dnlg dn lint \'ar:' \\i lh IIm l' or \\i lll concenrra tiou.Tln- possibilif>' for a dJallgt· \\i lll dOM' exists . howt·ve r, fo r ma ny reasons. and thes e an' dealt with in C ha p, 22 under th e utle of D UM' and Tim e Dl'pl·IJ(Il'll eit·s. Tl m mg!1011t tlu- majority of till' book, huwt"\...r , pharmac okmc tic pa r.tl1ll'n-rs an' aSMIIllI'l! llllt to (.'hungl' wt th either dOM' or ume.
STUDT PROBllMS (Answen to Stvd y Problems ore in Append ix n.)
1. G in 'lI IIlat till' t1isposilion l.int'l it's of a dm~ is t1I'Sl'riht'l l h~' a one-compartment Illtxlt'l , whid l O1I1'(S) of tilt· follO\\i ng statements is co rrect? 11.t· hal f-lift· of a t1 m~ follf)\\in~ tlw r apent ic doS('s in humans is oJ h r. the-refore, a. 111(' t·lim inatillll run- con stan t o f this dm ~ is O.l i 3 hr - I. h. It takes Hi hr for S' "S'.f of an i.v. holm dUM' to hI' clnninated. c. It takt ·s ~\in ' ;~s long to t'l imina!t· 0.3.5 g fllll c J\\i n~ a O.5-g holm tIClS(' a.s it doe -s 10 t'lillli llalt· ll..'i g folltl\\i llg a I .~ tIUM·. d. Co m pll'll' unnc ('lIIlI"l:lion np to 12 hr is 11('1"111"1110 pn l\itl l' a good t·slilllalt· of Ill(' ulttman- amount of d n lg ewn-n-dunchangcd. e . T ht· fr;tl'li oll o f the admi nistt'n "ll tloS(' elhmnated by it gin'n tillle is ilJ(lept'nde llt o f rlu- si....t· of til(' tIusl', 2. Cuk-ulan- tlu- foltfl\\ing: a. Tht' f"'ll-tiol\ of all i.v. tluS(' rell lajniu~ ill the Ixxly at 3 hr. when lilt" half-lift· is 6 hr. h. 111t' half-Iifl' of a d r ug, when IS% of th e dose re mains in till' hl xl)' -I hr aftN all l.v. bolus dost·. 3 , l'n-pu n - a st' milngari llunk pint uf till' f{)lIf l\\i n~ plasm a conceutratlou-ttnx- relationship :
C '" 0.9 e - 0 3.. 71 where C is in IIl WL and tinn- is in hours . 4 . A t1 m g tha i di splays OIlI··l'l Jlllpa rt lllt'1I1 disposition kmet tcs is adnuniste-n-d OLS a singll' !MIIIiS dust,. 1>t'pi(-tt'll ill tln- left -hand graph of Fig. 3--. are the plas ma con centrations o f d m g ohst'!yt'tl initially ( 10 IIIWL ) and 60 min later (2.5 IIIW!. ). Depicted ill till' ri ~h l hand j?;rdp h of Fig. 3--. is the tot al uri na ry excretion of unchanged d r ug IAt'" "" 60 mg]. Complete tilt" fig un- by drawtng continllum lint'S thai t!t-pil1 Iht' fall of d m R t1111('('lltmlioll in plasma ;lIld tilt' at."<.11Illulalioll of d m g ill u rillt' \\i lll tilllt' . ,S. F ru m 0 10 3 h r af!t'r a ,,)(l. mg ix . boills doS(' of dmg. lilt' Ave is 5 . 1 II1g- h rll ~ 111t' lotal :\ l'C is 2:1,4 mg.hr/L and tilt' (11I11 ulati\l' amollnl l'"l'n·It"lllln(:h an~t'll. :\r " . is II m~. a_ \\1lal I)('r<"t' nl o f 11.1' atl1l1i nisll'H'l1 tIoS!' rt'mains in th l' l x xl~' a<; t1 m g ill 3 hr?
"
CHAPTU J
II. Ca l("ulafto total clearance. c. Calculate tilt' renal clearance of Hu- drug. d. \\lmr's the fnl11ioll of till' dost" tlml is dilllill
C . 7.14 6- 0. 173 '
10
9 8
~
7
2- 6 .~ 5
°E
c;Eo;
~ " c -c.. ~
~
y
c 0 u
4
3
c.
2
o o
0.5
1.5
2
2.5 3 Hours
3.5
4
60
4.5
5
~
50
<> _E c _ o~ o ~
40
~go ~2 > y
~
c:;:
30
-" => o~
E ~
0,"
u~
y
20
"
~
10 0
o
2
3 Hours
4
5
CHAJ'ff R3
Call,dah' : 3. VOIIIIIK' of tli..lrihllhou h . ElimiJl
Pharmecol. n
,.we 3-02 •
Wf, _ 3 ;:522--52'\ , I g.~') , )
..... _
C
1•• -.1.0 -.lkw) h . Time lhrl
~lmg/lj
s.
I 137
I - . .. c.fhoIw 6 120
12 103
AffMo I•• • &4.1
24 76
48 42
1_".
n
Qo
23
12
144 37
a. J'n -p.tn· a ~ ' Ill i~ui llllnk pk Jl o f Ihc' plasma l11IK" lltr.llion of l't.· ftru.\OIIl- \I'nll" tin K'. E..tilll;ltt" Iln - !aoLlf·lift· of I.... d m~. h. Est ill\,;llc' ti ll' total A (:C of l1·ftria.\lJIll", C , C.ak·t1lalt' lotal clearance. d . C.ak' ilatc· tilt' , ,,Imllt." of d i'\t rilmtin n . n il' tlata !{i' 't"u in T abk- ~ .tn· lhc· plasma l1 111l"t-n tnd iuIlS of l'K.~IIl· a.\ a flll"-1ie llluf tillW aftt"r I." . ;tllm iui..tr.lliou of 3.1 m~ cocaine h~tt m('l.loride· In a subjt't1 . (Mnlt, 'u lar w.-i~th l o f cocaine h)tlrn t'b1oritle' := 340 Wmn1e·; IUo lt" llar ""t'i~ 1 o f ('(Il'UiIW := 31).1 Wmo 1c',) (Adapt t"C1 fn un C IItJ\\', \I.J.. Amlin ' . J.J.. RUIl, T ,I" Alli nson. A,J.. B ow..la-r . D.J., allli Fi'\(:luTlitll. ~I ,\\'. : Kitll'ttl'S of coc aine d istribution. •-liminatjou. al KI dlnmotrupk' d Tc'1". C lin . Ilh;.oIl."-'u l. Tl ...r., 38 :31S-.124, 1 9-~,) . )
,.we~.
"-- c •• _IJ.U. . . . . c.e.I_ a ..... 11. .lel•• . 0.-" 33 . .
Time lhrl ConcenIrahOn ~/U
01 6 170
0.5 122
10 74
15 45
20 28
25 17
30 10
Ol. l' n-pan - a '\('lIl i lu,.~a ri l " lIlil' p lo l of plasma lt ml"t' u l raliu ll versus lirllt',
b. E!otimah' ti ll' 1J1lIf·l ift' am] lolal clcaruncc of cocaine. c. G i\,c'n tl lal lilt' bud y wl'i~" 1 o f Ill(' slIhjt'l1 is ; ,'i k~, m ll'IIOI h' Ihc' \'Ullllllt' uf d isl ri· h utillll IIf l"tJl-ainc' ill l A Jt.
EXTRAVASCULAR DOSE OBJECTIVES The leader will be able 10: 1. Describe me choroderi5liCS 01, and the di!felences between, lirS/"Ol'der and
oZel'O'OIde1
ob-
5Ofption processes
2 . Oeiermine wherher obsorpll()O 01 disp<»ilion role limil!. drug e1,minohon, given plasma (orr
following d;/ferenl dosage lcems Of roulE!S 01 administrotlOn. 3. Anhcipolelhe effect 01 oflefing loleof absorptiOn, e'denrol absorption, clearance, 01 volume ofdislr'bution on the pIo:.ma cceceoectco and crrooet ofdnJg in the body ioIbMng eeo ceoecrcenee 0010
vascular odminislrohon .
4. EsllRlOle!he biOOYailobilityoi a drug. given ei!her plasmaccoceoncrco 01 ullncllyeXClehon
dolofo/bMng boIh exlt(M)SCUlo, and inlroYOSC\JlOI odmlni~ohon _ 5. EstllTlOle the relolive bioa.ooilobillty of 0 dll.'9. given ei!hef plasma cceceotctce Of urinary exclelion dolo following differenl 005096 forms OIIOUIeS of administration , 6 . E~,male!toe renal clearance 01 a drug From plasma ccoceoecrce and Ullraory e>lCleloon dolo IoIIowing exfrovo5CUIo, administration.
Fu r sys h ·mie.llly ad i ll~ dmhrs. abso rp tion is a pn-requisin- for t1l(' mr~ 'lIt i c adhity wln-n Iher an' a
n it"
imp,,(:t o f rate and extent o f absorptton o u lJott. plasma ouux-ntration andamount u f dm~ ill tilt' hody; tl.t' d Tt'\.1 of a!tt'mthllls ill ahsmpliull alltl d isposition 011 hull y k-vel-ttunn -lationshlps; ami Ihe methods used to assess plmrn \;t(:okindil' paramet e rs fmlll p lasma undurinary (Llta foll()\\in~ e xt rava scula r udnuulstrat ion. The term IJ;{I(I lA'lilaIJllity is l'CJlIllllollly appliloO to IX)jh rate ,lilt! exh-ut u f t!0l ~ inp ut int o tilt' sys te rmc em ulation. 11mm glJollt thi s book the term will ht· Iilllih'(l to tilt' extent of drug input and can 1M.' conslden-d as the Fraction, ur pcrwnt . of tht, aduuntsn-nd dust-, abso rh{'(1 int act .
KINITICS Of ABSORPTION 1111' oral ahso rp tion of dm~s ufit 'li approxiruutr-s first-o nlt 'r kiru-ucs . {'spt"li;llly when Wn 'lI in solution. Th e sam e holds true for the absorption of dmw; from llIany other extravascular sill'S i nd \l(li ll~ subcuta neous tiss ue and 1Il1lS(·II'. Unde r these ci rcumstances. uhsorptiou is d l' rdllR{' fmm 15 min til 1 lrr. OI"l"il-si'. tilt')" an ·lflllgt'r .
OWTE ~ 4
Souu-tinu-s, 11 dmg; is ahso rll("(l al t"s<;t'n lially a constant rail', 111(' absorption kinet ics an' tiu-u ('
B. 8emilogarithmic Plot
A. Regular Plot u
100
u
~
..."
80
'"s
60
0
~
D
"... 0
'"s
Zero Order
~
E
40
0
~
·E
First Order
.~
E o:
"" ~
20
FirstOrder
5
"Il ~
~
c,
10
~
~
'"
Zero Order
~
0
.~
50
~
D
~
·E
100
~
II:
0 Time
Time
t"lII:, "-I. ., " "" I'-In" ", .. f " ,",...",Io'r and li"t-<""Io'r al"" 'l l(inn I'I'"l......" .". ,, 'mik'l{>Ili thmk I,k~ ...f II.., 1" 'rn'Tll n '",,,i,,i"lI: In h.. ..1......."..1 ~ ',.I tllTll".
n.,.1<-.1an', ..\ . Il,~nlar .u,,1 H.
BODY lIYIl·TlMI RIlATIONSHIPS Comparison With an Intravenous Dose Absorpt iull t1, 'lilY~ ilnd ll'(lul."·" tllO' "1lIJ:,/Iit l/ dl ' eif Ow Il1.'ak {'OIIlIl;Irt"(1 to tha t s('("1I follel\\ill~ all t'(lua l i.v. bol us dost·. TIlt'S(' 1·0'1'(15 are portrayed for aspiri n in Fig. 4-2, 111l' rise awl fall of till' dOl~ couceutrutiou in plusma art' be s t understood by n'lIlt'III I I('ri n~ (C hap. 2, Ell. 2, p . 16) that at any ti me
dA d'
I·A
Rate of
Rate of
Role of
change of
o b$Orption
elimination
drug in body
CHAPIfI! 4
when- A" is 11M' amoun t of dm~ ,II rln-
ah~)'11ti ull ~ il l' n.' lIl ili n i n~ III Ill.' absorbed. \ \ 1lt'1l
h~' a first-onk-r p R ll't' S" ,
tilt' rate of abso rp tion i.. ~n'n hy kn-Au. Initially, wi th al l dm~ al the ahS()'11Iioll silt' and nOll(' in Iln- hOlly, rate of ah~)'11tiul\ is mamual an d rail' o f elim ina tiuu i.. zem, The-n-efter. ;l" d Ol~ is ahsorht'll. ito; r an- of ah<,uq llinn dt'1·n'il<'(~ , ",1Iert'a<, its ra te o f r-luntuatfon tncrc.ea-s. CUII''l'( plt'lIl l~'. tilt' di ITl'rt'IIl'(, Ilt.,· IWI'l'n lilt' I\\'U nm-s diminid lt's. If nwt'\"('r, u-.. ltlll~ il" tht' rate of OI!JSC IIVlitJIl C,\ ('t'l'(L.. thut of t'li millatioll lht' plasma concentr atkm cont inues to nw. E\"('l1tually. a tum- I ....... is rt'adll'll wllt"n tilt' mt(' o f t'lim inalioll matcht'li tilt' ran - of ah..u rplioll; ti lt' ("l)1l('t'ntmliou is theu .11 a maximum, C....... Suhst.'qu e ntly, lhe mil' of elhntnatton e:\('t'1'1I.. thl' rats- u f ubsor ptfon and tl u- p lil..lua conceutra uon dl,t:lim's. 111t' pe-ak pla...ma concent runon i.. always ICI\\'t'r folle l\\i n ~ ('\tm\"il"!11Iar ad ministral io ll than lilt' initial value fn lln\\i ll~ all ('lillal is. holus (lelSt'. In Iht' Iomu-r (' ''-'it' . at Ihe Ilt.'ak lilllP ~ ltllt' d m~ n-m.uus at lilt' nhso rp tion silt' alltl <,(llllt' lms been t'l im illalt'l l. whilt' ti lt' entin- c!US( ' i.. ill ti lt" hudy illllllt'1lialt,ly fol\(l\\i lll' rlu- Lv. di N' . Ht, u llcl lhe ()I'ak tune, tilt' pLt..ma ronce-ntration t'X('t't'lls that f(JII( J\\i ll~ L\". ;ulm illisi ml iull uf till' sallll' do...' hl ,('
absorption IIl'CU O
10
~
0
~
"
8
~ ~
0
-
';;~ .;:; E .5. -
.::>
6 4
~
E ~
'"
2
0.
0 0
20
40
60
80
100
120
Minutes
""ti""
t"iJl:.4-2. '-\' I" rin (6.''10 "'It) w.... ,.Imini'kn'ti ll.' all ;nl r..... 1.. ",. I M~ Il. ,.1 . ,,,1a' all ur,.] ... (OJ" n .. " ..."1.. in.ln" I,,..). " ' '''' '''11111 >11ca,,_ '" ,,,.l.t~ . lUlIl .. \c... .-rilti/: {If II""I",·ak l". Il, ·nlr..tio mII rnlo1I. .. .5,.5 j.I~ l l . ( ~ I , ..lifin l frum ,I... tLI... of Re... L,,"!. ~I " 1\;."·I,,,all. S., I I..m •. 1', .-\.. ;.... 1s l...Il"lT. S I)., ...I""'1>1io" l i,....Il...
,,,!:
A,Lq>tI'tI..1t1, p"' n n i"
it ll l
,i ,h., ("I~~J I '....' ItT )
EXTiAVASCl.J.AR OOSE
"
TIl(' h iua\Oiilahilil)', F, is proportional to the-t otal urea lImlt'r the plasma couceut ratiou-time curve (r\ Ce ) irn'sl)("(1in' of its shape. T lns must la- so . Heeall From C hap . 3 th at :
T0101 a mount eliminaled .. Clearance ' AUC hul tl.t' lul,ll a mollnl t·!illlinatt'ti is
2
tilt' <\111011111 ah so r])('(I, F . Dust" tllt' rt'fo1l':
F . Dose - Clearance ' AUC Amount Total amounl absorbed elimina ted
3
Thus. liIl n\\ill~ tlo,,-', ch-arance. and un-a. hioa\1lilahi 1i I~' llIa~' l lt, den-mum-d.
Changing Dose Unless ah"-''llt ion half·lift' or h io
po rtional ill(:n:',l"-' in phlsllla coucemrauon ut all tunes . TIll" value of ' "",. n 'maim unchaugcd. hilt C"",. increases p roportionally with dust·,
Changing Absorption Kinetks A!tt' ml iolls in t' illlt' r 'lhS()'lllion or di spositioll produce changes in 111l' ti me profiles of tl uamou nl ill IllI' h(ltly am i tilt' pl.l-sma co nce ntration, Thi s poinl is iUmt rolh"tI I,:,' tilt' tlm 't' situations dl'pi(1("t) in tilt' o;( 'lJlilo~~arit l\lll il- plots of Fig:, 4--3 tnvolvtug only a dlal\~t' in tilt'
Case A
'00
300 100
CaseS
CaseC
Absorption Elimination
o
,
8
'2
o
,
8
'2
o
,
8
'2
16
Hours t "i l(. ~1. A .1'''''''1:: (fn nn \o.'ftt" ri" ht l ..f ,lmlt Jo.·di,... at til<' a1"""llCi"" .il.. (It""..., !t"".apI" l ,I..~., I...· ;ollllin n"'n l " 'MI ,1. ~ TO 'a...... tI ", " "' l(Tli'n, lr"or tI,,· I..;ok l'u"TllI dro it l~"'Il" I , ;o1o"" l'liou (IoLoo.·1< lmd io .. f.., II'r pnll~,," tI..." ('hmll Ii,," (cul..,..IIi.... ). In CoIL'" C (Ihin l ",>r..pl, on lilli""" I, al....''1" ioll' II,Loo.·1< li'''' l r.." , h",i l' ..h", i"" lio." "" 1"" 1, I.·di 'l<· Il( .In ti( in pt..,,,,,, " .fI."t1$ a1""orpt"." r..tl,•-r ,·Ii," inat io •., ; l. ~"",, , tla-n- i. a ''' '! ,' h", inati.... nf dniK (!llrinlt tht' ,Wi,,,, pt..u... t...• r"l(' o( d imi,...lioll is ,h"",t ~· j..'n"oat,'r t ]..... 11 K" r..It' .. f ;o1""'1" i..." In all II,,,.., (.......-s. hitl\(·n liLJ.ilily i$ 1,0 ;0,><1 (.I.';or",,,"t" ~. ll!1l·h"n!:,,,!. c.''' '' ~ I"."n l l~-. tl,,' ;on'" , ,,,,,1.' 1' 11"' 1,1.," ";0 (~.""' '' Indit m · li nlt' ('\/1'\'0', k.. m~r- "Mli r>l( li",,,,r 1'10" o( II... I''f' 11m..' ~pl" ) an ' itl.'nli, ,.1 n M "..H ·C. Ilr tI.., Ii'''';or pit" . or tI,,· n" I.. d..t,, ;oll' 1lI.. , "'-1"llIl .."t'au't' II inl' V .,] or th.. ....1(' of ah" ''1" '''lIl, ;0""""" ,,1....,..+....1. '''I'''''' II,,· inh V ,,] o( I...· ra,....f r h",inatio", """..",t ..Ii"'i, I•..I.
,I,w,
3.
fKlRAVASCUAR 005£
CHAPTER 4
ah sorptio n half.llfe. All other fat1nr.; (hio' l\1Iil
Altsorpliol Rat,.Umited Uiminatio" Occasionally. ab sorpuon h:M-lift· is 11111<:1. IO Il ~(,( th an elim inalion half-lift·, and Cl<;t' C prevails ( Fi ~. 4-3). TIlt' pe ak occ urs lan-r and is lo"', N tha n in till' two p n '\1ous l'lN·S. T ilt· half-l ift, of dechnc o f d nlg ill tilt' hotly lIOW corre s ponds to tilt' ahMlrptioll half-lift'. 1> 1I ri ll ~ tht· rtw 10 llll" peek. lilt, ra te o f eliruiuation increases ami t'\'t'n lllall~', al tht· peak. e-quals lilt' rate of abso rption. Ilnwt,\"(·r. in con trast In tilt' pn.'\10 IlS situations, ubsorpttou is so slow that much of 111(" d m~ remains to lx- ahM,rflt'(l well Ix-yond tlu- peak tune. T Ill' d m~ is either al till' abso rption site o r has be en 1·!imin:I!<'(!; htt le is in rlu- I)(KI)'. In f.ll"t, d ll ri ll~ the decline pbaw, tt.l· d m p; is e limi na ted a'i fast ,LS it is ahsurllt'(1. ,VJ,\'OfJJtiorl ~~ fllJU: tlw ratelimit/'l l! slt?J. Under t111'SC circumstances. since the rate of elnninatiou ('sM'lItiall)' matches Ihe rate of absorpnou . tilt' f(JIl(J\\1 n~ approximancu (... ) ( "lUI 1)(' written
I·A Role of eliminotion
-
ia ' Aa Role of a bsorpl ion
thai is.
A mount a . . . body - (I) -I . remaining A~" '
In
10
be absorbed
5
A(1.,(lnling::ly, amount in till' Iltltly (am i p lasma ('()m'('lltmlifln ) du rinp; tln- dr-cltm- phase is
Distinguishing Absorption From Disposition Rate-Limited Elimination .\ 11 1.0 111-:1. d ispm il io ll 1-:1'lIt'mlly is m lt · · li lllit i ll~. tht' pr('('I"tlilll-: d i<;(.'u.\siun Sll~t"lil s tl llIl e d. ll-
lilill II lay Ilc,('f l h i lit, c'sl'rd '\t'(1in ill!l"llrdi ng tilt, II lt 'a ni ll ~ of Ilalf-lill· del('mlillt't ! fmlll the t11·diIW pha",' fo llowi ll~ t'\tr.i\'a\('lllar adminh lralion . ( :o llfu\ inn is a\~lidt'tl if lhe d n lg is
,.
CHAP1H A
al~l ~\"en intnl\"{'llollsly. III pml1k'-'.IIIl\\·I·\"{·r, i.v. dusa~c' forms of Illany
fur eliuical IISl' . Distin"..nishi nF; ht'l Wl'C'1\ ah sorptioll ami d isposition rate -limitation s is aeh il'wtl by altt'rillF; the ab sorption kiuet fcs of lilt' t1nl ~. This is most n'adily accoruphdn-d hy ~h i ll ~ the t1mJ{ t'itlll'T in diffen'llt do sa!?:t' fo rm s or hy d iITen'nt mutt's. To i11l1stmte thi s po int , l'ulisitiN data fur t1wuphylline ami pC'nidllill (; . FIMMI nnd wate-r inHuc'nl't' tilt ' oral ah"': lIv tion kinetics of thc'tlp hyllinl' hut nul t "c~ ha lflife elf tht, dc't.'lilll' pl.llw (Fi~. 4-4 ). li e n ' then, dispnsitioJl rute-linuts theophylline eliminauon. In contrust, fur penicilhn. \\ith a \"('l)' sho rt d iminalinnllillf,life , Intrur nuscular (LIII.) ahsOIVlioll eanlk,(11lllt' mk·limitin j!; hy fonllllialion of a sparingl)' solnhle salt (F ig. -1 ~5 ) .
10
1-"11/,. +-4. t h'. 'l>l l~
8
~
51111 ",I. " f ",...k r . 'MI ,..k-n on lU I " ln l>l~' _t" m,.d , (0), T akin1/: tiM' ,..ltJ.'!, "'; 111 2lJ mL of .....w. ' "' "" " "'Ilty ,1" tI ", (0) ~ull ...1 in "'.... ·r ..h""'l'h,," tha" t.,k",!: tI ", "ith Itw Il&mt' " >1"" ,,.
4
e
~
u c 0 U
",...Iia"·~· li>llo...i nll: .. .tantLordiD..1 hill:h {1lrhnhy-
2
, I',d. - tlM·..l (el. D' ''' 1'il '' rlifT.. 1'f'fK'M In roll", nf a!>...,rl'li"l1. I.."",·....r. th., It'n niruoJ h;Jf·lif,· w~ II.., ..."... 1".3 h.."n) tl...n-f", e . il l. tI..· .-li miu "li,, " 1....lf·lif.· lh''''l,h yili"t- ( I mWl • .5.5 f.l\l l. ( " ,..d . 1". ..1 (nUll \\'..Il l1l~ P.G .• l.yo I_I ~ , enliJt. \\".A . of.1ire a,Ml IIniel un an,l Trudo!a. G .A , l" fI" hi"""".;I,,1>11;1,- of 111......,11) 111ne . C h n. I'h" rUl;U'11. nM'r " ; ,475--4'jll. I~~.)
~
s
~
~
0
~
~ ~
E
."ttI.
or
'" ~
"'I:
,,"';llO
§.
.~
c<M'I.unin]( 1.111
tiN , .. rio.. " .",.. Iilin'" _ i\ IKC oq>tlo n .,f 1I"''1>1,., lIi,,.· " ,. . .1 r~>i, 1 .. ~ ..·n tI... ,,,h it.., "" ' 1'1 ' di. ...>1""11 ill
6
c
T" ., lal.l<1'. .-;00;-1,
m,",.'''' 1'1' ,..k.... I,> 6 1"...Jlh;o-,. ,jun" ~· n "11 '
0.5
~
.ss c,
0.3
4
0
8
12
Hours
5
c 0
~ e 8c 0
P·I.M.
1
f"ri""
_
';; ~ ~E
"
u-
.~
0.1
t:----..
I.M.
c,
E J
~
J!
HI!:, t--S . "' '' li<:illin c: (3 1fW\l() ......, ... Iminio· h,,,,..1 intTII.mmn,Larl" to I 'u iI" lni1;'''' "fIo, 1 raI e- Ii "';t~ th'l"lSilk'" f,~"",,1111: i,,tnun " .....' wr ...Iml"i.t ratif", trl tI......1'.......... "" Iio-It, t'ltIl '''lly t... m...It· by K*'i"!t l""..iMllin (; intr. ' .. """.Iy. ( I mWI. - 3 .0 "M ). ( Mod ili,·,1 f ru m M"",,,. I> F .: o"tli"" ..f Fu lld..,..... 'I"" 11"mll......1-
0.Q1 0
6
12 Hours
18
24
or
h.",
or
I'..,
' ~'.
e h" n... C. Th..rn...... SprinKfir1t1.
II ~
19.-') 1.)
n n AVASCULAl1 rose
CHAPTH
~
0
10
",,,I.., tl,,' I,l"",;/' .. ",n'nl.a, ~
Fill:_4-fi. .\ ,,,,, (,,I.l •.0: ... ...... tl..· .on-..
" ~ I ' M1 " " , in (,I.-Mall'" j " .
,..,"-,''',,, 1,. .."....11"..·. 1,,1' Io:r"1',/, ),... . .("lel, ••", · p.......II" ,1,.,1 ,,( tl..· .. ml n~ 11>I...1Ii",-) ..f" ·r .. " "l:I, · .·\lr..' ....."1..1 .1. \ \ ';111 ''', d ~Ul~" ill "I>. ""!,h",, Li'", tin 1... " 11 ",, , ah"''l'Ii'' '' r.lt,!' rnhl.· wit l,
l li,..·. I. ,tt u lIl l::r..I'IoI.
lo",,· ) (, .. "'
110." ".It<- .. f ,·I""i".di" ,,
<
1 Ii'..-. I..,n"",
l" I..· 1<",,-• .,t Ii". 1"'1 ,,, I...... " ..· C.. ·.,I<-, Ih.... "f tI,,· .. 'IIln,I II,I...1
1:'''1,11 \
j, ,~ .... ·... , .. I
tI,."
'" 8-a,
5
0"
2
~
u
~ -
=E 0 _ ~
E ~ ~
1",,·. I.. ~ Ic " " 1:'-"1",1, .., II..· Mo' " ","I.., II..· nor" "'1" ,,,.1"'1:: h,..·". f ' I"....· ....10· (.,n ,... """.
p"."..
1000
h." '''1".,1 I" tl,,· .10 · (" F;( . "~1 1. 11..· ,10·· ,·rt·.....· in "!.-,...",,, " , 11.., I'O"', L '''' '''' ll l r~ · 'M'" ,,, I.· I:"'~r,'r ,,,..I'n ' ..... r ,,' " 1;'10" h UH" h ,,,l~ , hl:h' l ~ ,MT" n'''! h,·",). 11..• I" ·,,l li UH" '1( ' . " ' ''' " I..·" ,I.., r'l" '''( , 'loU"'~'!" """'I,,~l. ' h, ' r.." , .,f " I"" ,!' I " '" 11" '11" 11I l:'''l'h l. T Il<' 1,' rn,;" ..1 , I" ..• n·II...1- 11..· ;,,,·n·..,.. I,·I""",,
500 -
~
Absorption
200
§. 100 ~
'"'"
/ ' / Elimination
50 20 10 0
4
8
12
Hours n"t lm ·lio u ill dl'ilf;llln' und. IWIll, '. ('!illlinal ilm run- coustaut , a gn-a h' r a mo u nt of t1 nlg IIHlst hi' a h\ll rlll "ti. am i lI lt' ptl\lIIa l'lIll" lIl ra tillll 1I1mt Ill' gn'alt' r pri o r 10 till' li lllt' wheu th,' rutr- of dilllillalioll ("tillais 11.(· rate o f ah\l)'l)liuli . As SI.(I\\11 ill Fig. ·1-'j , tl.,' t,\('nls a n' d in-I'n 'nl wln-n an illl' I'(',I-\( 'l! volunu- (If di st rihulilm b n 'sl'NlI\sihl(' fur a IUllg(' r (,Iilllinalioll l.a1f·li f(,. Um ll' r 11ll'\(' r-i rcumv tances tilt ' t\ UC is til l' s.uue if h iu;l\"ailahilily and ('(1'011'.1111" a n ' 11II(·ha ngl,,(1. 1111' peak IJ('('11rs late-r ancl i~ 10w('I', htlwt '\I 'r , \\'itl. u b r):t,1' \'UIIlTlIt' tlf distnbutton. 11I0 1'(' d m~ IIIU\I IN;' ahsorlN;"t1 (,('fo n ' 11.(' p l.l-s lIM{,(lIIl"('lll ra tioll n-acin-s a vulue al which Iht , rate- o f eli nunution ((.'1. ' C ) (,,( plills tlumit' u f all ,mplio n: the- ubsorption run- is 10\\ 1'1' tlu-u ilTltI so is ti lt, plaouu 1'lllll" lIlralioll .
PreetKting Changes in Peak Qll alil"lin- d l a l\~(,s ill C".... am l t...... •rn - diffu-ult 10 pn-du-t whr-n ab sorpnon or d ispositioll is nhr-n-d. T o f..l'i litalt' t h is pn'll idiulI , u IIII'mlll)' aid h,l-s hl"t'li foun d to IN;' 1I<;('fl1l . Til(' h..stc prtnciplr- o f IIJ(' lIw tl uMI ( Fi~, ,,--Ii) is silllpl("; 1l11\(11"])tion iUl'rt' ;L",-'S <111I1 dilllimition " ('('n ',l-\('<; li lt' amount uf t1 m~ in lilt" 1'N'Nly. Tlt l' f;lslt' r III(' ahSl:I'l)liu lJ p n ll' '<;s (ant';Lsllrt"t1 hy ah "'ll'lltion ran- ("(lIIsIOlIlI), tilt ' g rt';ah-r is till' slop" of till' ah\ll'l)tin u lim' , ;\1J(1 111t' rou ve-rw-. 1111' fasn-r tln- ('!illl ill;llioll P",I'l'SS ((,Iim iualillu ra n- 1"(lmt.lI1 t), tIll' sh"('I)«'1' is till' t1.'('!im ' uf tilt' ('Iillli llalioll lim '. If a h\lI'l)lioll raft- constant is illl·n·.lSt't1,Ihl' 111'\\' poi nt of inlt' N'('tiflu iml it'a!t's t hat Iw ak anmuut is illl·n "lSl,,1 und thut it lll'('ur; at ,111 carln-r lillit' . If t'l illlill
t_.
CMAP 1E ~
.,
A
">I"",,.
I-l K. " _7. .\ f\>.,,(,,1cI i'K.,.,·.....· III ,I.., tlf ,1I'l ril..,h.." (."'" ........ ,,,,,fuM ;'Il1'1·.....· ill tlo.,·!im j" ..ti .. " I...I(·l i(. - ;on<1 ,I••l",~ . tl". Ii "", .. I
"foid, tI..· 1" 'oIL pI..,,,... ""..H ,lr.dio", tI(U,I' ... 01<,0.11".... "'I' j(ml>l,\ .... "1..." ..1til 11... (. ,u· I n ,l , 01",,' n d lil m
",Lt.{ li".. l ;tll.'r .. ,i"I:'" ,'\I r..·
"IM,J,....·. With "" d,.."\,,,· ill ,-I.·at,nM. ....n'" ' ,ullk" I",. ' ar Il.·"tr"'Ii.. "·fj"... 1,10.. 1 ;. " " .
,;t...
li""
'~'''''I:', l .m.t p l nllK""tr.. i, 11,, ·n·I ~· n-. ,I"n'd ISo ....,,"'· "I" .. " ...." , , ·.,lr.ll ...I1. •" t.' "f o-li,,,i,,.oIic,,, i, i ",tial~' . 1. ,..1 (I,.I.,n..1 [illl ' , I....' ..m I(r"I", >. I",1,i,,,, -,I..· .." ...." '1 ,·]i"';II"I., 1 ;, II..· ...." III ,,· ,L",·I. " f •.fi"'I".lIiI.......·,,· ,,,..I~ i. " " •., II."" ,I.", "f ,I..· ',lI.l,,>I lill.. ,l IUN', h"tt"", 1(,,,,,11 1.
1000
,.1,·
500 _ Absorption
~
200
S- 100 ~ a:
/ / Elimination
50
r
20 10
0
4
12
8 Hours
. '11:. 4-8.
B,'
,
,
,
,,
,
, ,.
,
,
,
,
Me mu ry aid to ;u... u du. np:l'l in pt'a k
Iim.. . nd prak a moun l in the body. ftl'rnlravalMIla r ad m lni l tnatlon o f ;0 IrinKJe ,) n . b. m rpt lo n or di~i1iun " . It..red. n... tiYr pt'u 11m.. anU Ih<- I't'l.o.tiw' ["'a le amount art' tn-
,
dicalNl by lhoe Inlerwctlon of the ahwrp hon and
..limlnaU,m lin... (A) with .Iopo-. n-p....... nlinp:the
A
a h....pbon a nd ..lImi l1.lllio n rale conttanll.~' 11\~ly. p....Jic.1lo nJ (OT a n IIKTt'aord a hso rp-
n...
l ion ral e:' co nsta nt (colored dashed line and poi nt Bl and an Incn-.ur
C
10 a. Sf'lt duo nKM In pralc ti me and pt'aIc COlKTn-
Time
lra lion wi th aheratlo n in druJl: .hoorpuon or
pm iUo n. Am. J. Pharm .
duo
ea.. 46:154-155, 1~2. )
vnlunu- o f distrihut ion v..111M'S a d('('n ' ;l<;(' in pea k concentration , and the cnuus e-xplained under Ch'UlWI\~ Dhpusitinl\ Kinet ics . Spt"<.ifil· rt'l aliu llst.ips for t'stiIl l
!IIe l'l'il'" i ll \"(' I"!\(' ,
ASSESSMENT Of PHARMACOKINETIC PARAMETERS lI ow sonu- paralllt"h-r vuhu-s art · t'stimalt'tl follo",i ll~ t'xtm\ll-"l."olilr ad ministra tion ran lit, a pprt'('iatt'(l hy {"Iln si dt' ri ll~ ho tll tllt' pl.t\ lIIa conceutratkm -tun e (·U ....es in Fi~. 4--9, ohtaillt'(l
CHAPTER.4
42
2.0 Fl~ . ~9 .
,e- .,
\ 51"'" ""
, ~ ...... i. 1/;i"'" ;,,' r"""'''-~ II...I~·
"'K IIIr.J I~ (0- .
"-",,m'h' ,
" ..1", ,.1
·0) h. tI..· '
1.0
;,,,... 11,,· t1nlj( i. It·•• loi.w..."il..IoI.· 01",1 1 ",,, n ' fn ,m .1..· ",,,,-' l,,,i nh.. ti ,,..l
.1<""1:-
In.d , A l'.mJ Io·1 ,10...·li'.... 1.."" "H"r, inopll<" lilA ,Ii., ,,," il ;' ''' i. ' oI!t". ]im ih " l: ill
""d, i n,f..lln '• .
0.5
00 0 0 0 0
0 0
0.2 0.1 0
4
2
6
Hours
y.w
hlvll
1. D.ttI 0Ith It)' Dlfte_,,'
newl... &tI.I.I........... SOO _ . . . . . . . . . hi
. ~(),t.I"
l'\A.'.M.Il. o,.o..l'"
Cl,Wl.U..1N( AAlOJll
!'WJ~(
eon InIlO.-enou~
Intromuscular
0 01
"""
DECAT PI-t.o.Sl:
'....A>
,-,
76 74 35
190 185 193
E lC tn1DLNC ~O
l""!ll
152 147 70
r(lllm\in~ i.m . and u ra l adm inist rat ions ,,( SOl) mv; of a dnl ~. and in Tahh- -I- I.
tln- mld itin ll"l tnformatton
P10sma Data AIon. Hinn n.i1l1h ilit,... Sup plt'lIlt'ntal dill•• [mtn L\'. ad lllilli"tmtioll allow ('a l('u lal iclll nf hiu;wailah ility. f . n il" tol ot! Ace fullo\,;nv; extravascular adminis tration is d i\itlt'1l by ti lt' are a fnlllJ\\ill~
whk-h ass tlllWS that
d n lnlllCf' rrm atnx olllMtm t , is .l\ fullows :
In tr.t\"(·l\ou s (i.\,,) (10<;(' Do~, , ~ .
= Clearance ' A UCj ~ ,
6
E,l m\·'l\t'u la r (I'.'·.) ill, S(' F. ~ _
. Dose. ~ .. Clearance '
AUC. ~
7
8
Fo r ('xa rnpll', app m priatt'iy SlJ ltstit ut i ll~ till' an-a 1II(',l' urt'lIlt'n b ill Tahl(· -1-- 1 illto ECJ . S
intl it-,Ilt's tha t the- bioavaila hility of tilt' LIlI . doso is 97'l . Virt ually all dm ~ illjP<.1I"{1 into 11111Sd t, is abs orbed s~~tt' lIlitM.tIly. III contrast. only -16% is btoavailable w hen drug ts ~'1.'1l ondlv in so ilitioll, A'II alll'nlalin ' method of ('stilllatill~ bioavailabthty. w htch ~vt's the- same answer, is to subs titute tilt' vahu- fo r clearance di l1."(1:ly into Ell. 7, Clearance can lx- es tunan-d fmm bloo..1 (or pb,sllla ) data foll()\';I1~ euher an i.v. bolus dose or a constant-rate is . infus ion (C hap . 6 1. Rl'1ut it t, hitl(lt"fli!"I,il ity is dl'l enllille..l w hen the re art' 110 i.v. (lila. Cost, slahility, solu. hility limitations. am i polt'lltial hazards art' major n-asons for the leek of an i.v. p rep aration. Hdati\"l' hi();1' 1tilah ility is det emuued hy ccmp an ng different dosage fon ns . difh-reut routes of admillistrati oll. o r tliffl'n'llt condutons (e .g.. diet. di ~·a...e state ]. As with th e calcula tfou of hi();l\"ailahility. d t'am lll'(' is ;\.ssUIIll'd to I)f.' constant. T hus . I ;lkill ~ the ~1'1U' rall'l'it· :
F" . Dose"
=
Clearance ' AUC"
Amou nl
Totolo mounl
absorbed
ellmlnoted
9
Fe ' Dose e s Clecrcoce . AUCe
10
fA •
11
Relotive _ bioovoilobility Fe
(AUC6XDoseB) AUCB Dose6
TIll' n ·f('n 'II('l' d nsap;l' fnn n d lO'i('lI is uSllall>' th e om' with the highest hioavai lahil it>·, th ai is, tilt' on..' h· o f till' oral doS(' is the n -16%. If on l)" two oral doses had I ~ '(' II ('fllllpart... 1. Ihey nmy havebe... ·11 e-qually, ullx-it poorl y, hio;l\'ail ah lc·. It should I)f.' 1I0h'i.! that all th e p rt'l'l,
CHAPTH 4
Fort unat e ly. tl u-n- is a su ffid l"lll hod y o f dat a to determuu- a t Il'lLst till' I'limi na tio ll halflift· of most drugs. Failure o f food. dosa~t" form , and. in till' I' \iullplt, in Fi~. 4-7. route of ad minist ra tio n to arTt'(.1: Iht· lNlIlillil1hillf-lift' indicatethut th is must ht ' tilt' r-lhmnation halflift". Also . a d nl~ is "ftt'l\ fully bin,lva il,lh l!' (1" = I ) From i.lII. or sllll(.'uta nt't ills silt'S, Ih·m"{·. t'!t·a r.lllt"{· can II(.' (:ak11Iah 'tl k lJ(,,\i ll~ an-a (Efl. 3 ). am lt lw vulunn- o f d ist rih ution t";1II lx' t"sli malt'tl tlIwt,t ht' t·limina tioll Illllf·l ift' is known. Consider. fo r t.xalllp lt-. just tilt' i.lII. dat a in Tahlt, -I-I. C k -arane-, uhlaillt"{l hy t1i,i din~ dost, ( 501l 1ll ~) hy Aue (7.... 1Il ~- hr/L) . is 1.1 Lznun. Di \ldi ll~ dt'amll<."{' by tht, el im inat io n mit ' cous taut ( U. 69.1I 1 ~,) min ) ~\'t 'S tlu- \1111IIIlt' of dhi rih utitlll. in t his t' LSI' :JOll L. Pn...i ons!y. a r.lIlKt· o f likt'!)"ahso rp tioll llillf-livt's W,LS II\lokt l. TI lt' v,llm's wt' n ' t'Sl imalt'l l imlin'(.1:I)· fn nn ptLSlllll t'tlllt'(·nt mtio ll·tilllt' data. Dtn -ct I1lt',LSUn 'llIt'lits uf llhso rp liOlI ktrwt tcs an' illlpos sihlt, ll(.'l.H dllst' p!,Lsma is l ilt· sitt' (If n u-asun-rueut fo r both ilhst lT))tioli a nd di spos itio ll. To calculate til(' kim-tics of absorpnon. a nu-thodmust tllt'n 'fn n ' 1M' dt...i st'(! to Sl'!l;Ir.lh' t hr-se two p n l(.'('sst's. T \\11 n ,lal in ·I>' sim plt, IIlt'tll1Mls for ad lit'\l nK this Sl·llilr.lliflll an' dtscusscd ill Appl,IItIi.\ I-G
Urine Dot. AIoM G in'lI o nl)" uri ne data, m-i tln-r ch-umnce nor \Ullllll(' of drstnbunon l '1lI1 1M' calc ulated. If n-unl c k-anmrx- of t1mK is constant , mi t' u f d m K l'xc n 'titJII is I' ml'urt ion a l 10 its pt L\ llla concentration, ami IIndt' r Ihl 'st' circum stances . thco n-tunllv. excn-tiou mit' dat a can II(.' rrea ted in 1I IlIl11111t'r sim ilar III Iha! fOT pl.uuur dat a. In l' r.tl1:'k t " dllnll~ l ilt' firs t t'tl llt'l 1: io ll o f urme-, usllally I or 2 hr a ftN drug administratinn, ahst lT)ll ioll o f lll,lIIy \\"t'II-a llsm IJt"t1 t1 n lJ.,'S is \irtllillly fiuislll,(1. A shurter t'()IlI'l.1:inn Inn-nul is Ilt't't lt'l] 10 d larat1:e ri v:e- ah st lrp tioll kiuelit."!i hil l is tmpracnca l bl'l.";I1ISt· uf ill('O lllplt'tt, (' lIl pt~i ll ~ o f tilt' hladd t' r and a ll inahility o f it sllhjl'l.i: til p mdll('t' a uriru- s ampk- 1111
1-, ,,. ....
B
'n
10. 11,,· ,\ ["C "p t.."" . II..• tim.· "I" ",:t~lm ·Il,-,· ..f tl ..· I 'i~ ""'1 .." ..., ." . Ir..li< .." c....... n 'Wi", h . ,I,,· 'nl..! .,\ t·C " 1"""""" tl..· .."...."' t .·li ",in...h, 1at I ......
n·I••t,,", h' II,,· l<Jlal .." " ..,,,t ,·l""inat,,1("''t' t' il:. ......1 ).
/ C_
ult i",.d.·~,
6 c
.~
;;;
E 4 u c ~
0
" 2
o
o
3
6 Hours
9
12
CHAJ'T£ ~
os
4
Fe _
Aex F · Dose
12
T1lt'II, Ilsing: lilt' SUhSt'ripts :\ and B to d('noll' IWII treatments, il follows thai Ae,,-•.Jfe
13
Fe ' Doses = A• •.elf•
14
F... • Dose... =
Amount absorbed
t, Fs
g
Ictcl amount elimina ted
(A•..A) . (~) Ae"" s
Dose,.,
15
1111' ",tioof till' dO<;(·-lIonnalir.("I1('u mulatin' mnouut (,:lOl'n '!l"ll um:lmuK("I1is 111t'n·fnn· tilt' ralio uf tilt' hio
mwl ,52 l ll~ ) X IOU], :\o!it" that . ,t~ l'Xpt't11"l1ifJe is con stant, thi s \ -al i li' is th(' S
f'tasma and Urine Dota T Ill' n 'nal dt·;lr.II1(,(· u f a d m g: r-an 1)(· es tilllit!("(1 when bolh plasma an d urine da ta exist. TIlt' app" );\l'h is idt 'nti l";lllo thai taken fur an i.v. dose- (C hap , 3 ). Sinn.' no kllowlt"lI~(· nf hi();,\"ailability is n-qui n-d. til(' ('stimatl' of n 'nal ch-arunce From combhu-d pl.l~lI1a and umndala fol1()\\; ug: t·:l.lm\·;L"l'ular udmitu strunon is us accu rateas that obla illl,(! fnll(}\\; n~ i.v. dmg: ;u Inunivt rollion.
BIOIQUIVAIINCI 1..IWS lIl,mda!! ' th at nt 'W tlnlg: product s ht· Slife and (·IT('l.'lin', If a IlI'W pmt.lul1 of;l t.In1g: lilt' Sl IIl1\ ' Illolar tlo....• and is of sim ilar fonllulat ion to mn- aln-adv sIJO\\1l to 1)(' S
..
C HAPTU 4
In p ml"liet·, C...... um l I ...." a rt" ('slimill("(l [mm till' I li~lu 'sl ('UlIt'\'utm!iull measured and
rlu- linn' uf its occurrence . As till' plasma coucontratiou-time curve is fluitt· flat near thept·ak a ll tl h t"(';lUW uf assay variability. til(> vahn- of t...... dlll'O(' 1I 1ll;1~' nul lx- a ~ull(l "·(In·· v-nta tiou of II\(" act ual value. Furt hermore , thl' iK't.' lr.ll·~" o f tln- t""'. ('s lima!t· is Iilllih.J hy silln plt·s II(' i ll~ o hla illt"tl o nly at d iM-'n'h- times. nillt '(llI j val (,Il('t 'I ('still ~ usually urtses when a pa l(' l\! (Ill an Innovator's dnlJ' ex pi re-s. O ther
manuflu-tun-rs lIlay tlu-u wis h to ma rket tln- sam!' formulanou of tilt ' dnl ~. Formulations thut are hio('(llIi\'a lt'1I1 wuh that of ti lt" innovator a nd ht'ari ll~ till' 1!( 'II t' rit' name o f till' ( I nI~ an' ( -;1111'( 1 ~l'/lI'ric products. Bil)l"(iuiva lt'll t'(, tl"slin~ is also rfomu-d dllrill~ the t'(IIIN' of d t"\t'!"pIlIt'1l1 n f new drugs. wh en a foruurlation is d mll~t'1 l. or wln-n tilt· sitt- n r I1 wlllOtl of tuaunfact un- is a lk n't!.
r"..
STUDT PRDllfMS (Answers to Study Prob lems ore in Appe ndix II .) I dt 'lI ti ~v t'"el. of Iht' stateme nts below tl mt an' corn-et (see- Fi~. 4--.')). For Iht, one. n r mere, that is lint t'OITt't1, st,,!c' wb y it is no l or su pp ly a llualifit'a!inll, a . All utllt'r paramdt,rs n ' ma ini llg tllw hallgt't l. li lt' s!IJ\\'l'r tlu- ahsorpl iull p n l(' '''''s , lilt' h i ~l 1t' r is lilt' peak pl. l.s ma concentration afk r a s i n~lt· oral d n....-. b. :\ fiN a siug!t' oral close. 1II 1 illt'n 'lLS(' in hin; lvlliiahilily t'tlltst'" the pe ak ti me In sllOrtt'll. e. Fur a ~\l' 1I dnl~ in a sllbjt"t'I, ..\ UC is p m)'nrt itllla l to tilt' amount of t1 n l~ abso rbed. d . If kll < < lc , 111t'1I the- terminal slo pt, of tilt' p!;LSIIl'1t'llllt"lltralinll \l 'rsliS tum- t11rVt' n-th-cts «leorpnou . lil lt cluntnatlon. 2. (:ralTlIl'r d al. (( ; m lTllt' r, c., Juhnsso ll. ( ; ., a nti Sji~n' n , J.: I'ha r m;l('l,kill t'l i("S (If prot"1till;llIlitlt' lut ravr-uonslv am i omllv as conventional a nd slow- n-h-asetable-ts. e lin. Pharmacol. 11 1t'r. , / ;'":-114-12.3 . 19 • .'» ), in l'\ltlua ling tlifTt' n 'lI1 dosagt' forms n f p n ){'ltinm nid t', uhla iTlt'11 the fnlt()\\; lIg ,.\ l:C and ('u lIlu lat i\'{' u rine {'u'n..tion {la ta Hste-d in Tahlt' -1- 2 .
I.
T.~"4-2.
eccn .0 0' FOIm,,101>Otl 1 f Ol m,,10110'l '2
cos
-o:
t .«:t HlO 10-48 "'I to-gl
IWOJ'{I
'" 500
("'9"'/1)
13 1
332
1000 1000
200 10 0
586 554
u. E ~ l i llmh' " olh hioi.t\1tilahility a m i rt,lali\"(' hioa ntilability of Iomudatton 2
Irom hnth t', tilt' t!uS!' "t!mi nislt'n'tl ;Int! a ll n tllt'r IMmll ll'h ' n; ( a"ll lll~ f", ktl , \ ', ami C /. ) n ' ma in \l llel.a l\~t"l. l . ptl\lII
.7
Time
Time
a. F dl'('n ',l'>("(l
h. h, Incn-ased c. CI. mcn-av-d. k Increav - dhy ~1I 1l(' (idor d . C l. ck-cn-ased. k d t'('T!,it'>t't ! hv same Iactor r-. v i1wrt'a.'>t'd , k /l; j.( nil st'Il;lrah' O('(;:L"io ns . Tahl(· 4--.1 lists lilt' saltent fi lld in~ o f t ht"w studn-s. Tlu- nu-an wt"ighl uf ti ll:' pa tie uts wa... 60 kg:. T.It•• 4-3. M_.. AU~ Maxi• • • PI. . . . CeIK Iryth p.I I S el DI _ _ a..... I..I .
_.",
I"'!ravenous
3010
Scbcccrecos
1372
'--...::I _
~
"'"""'"
«c
~S!~"TO-'
0
f~
( U
•
~"""""""I'QhfI"'"~nglo _ ., _ ...... I,." I>oc<j ~
wa> "' ''''
COt<EN1lA10'1 .....",
4 17 40 ,5 ><'* H C
~ "'"
~~
C ,
t~
_ ••1HI ' ....1...1H.If·I'" ef 'onowl I.•• olld •.c. A
CO'-.a NTV.!lON
' ''''''' ..,
5 mm b 17.
16,1
" "
"",a,
(>
"""""
8 . .,... 5ctooooalo . M
_
67 ....... col
_~
'--
<>
a. Dd l'0I 1ine tilt' d l'arann ' am i vclunu- o f distribntjon of this d r ug. h . Calt-ulaft· tilt' hill;l\'ailOlhility of ('l)1 hropclic'li n aflN s.c. atl minisl mli o ll in tl.t'....· patk-uts. lI ow lIl i ~hl }UU exphdu }ullr answer? C', Tln- muxin... rn ( 'o ll l '(' ni m tillll o h.st' r\"t"(! wus uun-h Iuw('r after tlw s.c. do...-. II nw dn )',," l" plaill lhis " h >;l: 'I"\'alioll? .5. Clnunn-r uud Holx-rts ( W ~51 stud ic'(l lllt' t'fft '1. 't of del ayt't) (osoplmgt·al trans it O il tluabsor pt iou of ;\c'{·!,"nil lllplwlJ. Ead. o f 20 pati ents ;1\\1Li ti ll~ (~.lR.li 'K· I·llt l.dt·ri7..at iou swalloWt..t1 a single' tahld ('(m ia illilll?: acetaminopla-n ( 5()(). m~) and bari um sulfan-. T Ilt" fin-t J I sllhjt'(:b swa l1ow(... J tll(' lahlt,t while I)i ll ~ t1l 1\\11: in III of these subjects. t ra nsit IIf lilt' ta bid W ,l S d t,la) l,(1. ; l S \i.slIaIi7J'(1 hy lluorosco py. In th e ot he r 9 sllbje<.1: s who swullowt't1 tht' lahlt'! wh ilt' sta lld i n~, it ent er ed the stomach imllll'(liatdy. III both ~rnll p~ tilt' ta bid was ta ken with a snffid t'llt \~ )l tl llw o f wa ter to past" swalltl\\i ll ~. Table 4-1 Ih ts Ih t, a\"t'r.lJ.(t' ph sllla ao-cuutncphen dat a obtatncd ove r 6 lrr a ftl' r s, m lluwi llJ.( tilt"
tahlt'!.
••
CHAPTU 4
T."I.~ .·
o
20 30
40 50
o
50 58 03 47
03 I 1
01 19
28 32 39 31
00
4.1
Q()
3.5 28 22
29
17
18
18 15 075
15
120 150 180 210
"-..c_ _
o
2.1
10
240 300 o--
~ ~ _ ~-..
CJC
17
07
f-'d~~ _ .,..,..-_""'--"""""
n..
~
n- .l7n_
10. 10 85
"l:>.. "'9Jl .. 0
(I .....
a . \ \ "hat d Tt'(.1: do('~ dd ay('(I l's()pl. a~t·al t ransit havl' 0 11 the slx"{'(1 a nd extent ( If ahsorptiou of of this d m~? fl. Bt·sllyah d ul. ( Bt'shya h. S.A., Anyanku . V.• S ilhthya lliUllhiln. n., Sharp , P.• and Joh n. ston . D .( ;.: 111l" d Tt'(:t o f SlIht'ula lU'()IJS injec t ion sitt' o n ah smp tio ll of hu man ~rn\\1 h
hormone: Abdomen \,(' fSUS t hi~lJ . Clin. Endocnnol.• J .5:40H- H 2, H~Jl ) examined the l' lTt"(:1 of s.e. illjl"<.1in!l site Oil III(' absOIvtioli of lm mun ~n)\'1 h hormone. T ah le 4-5 lists till' meun seru m rmrcentrutlons ill I I subjects ohserved dunug the first 12 h r a fle r thr- adnnmstration of ", IU (illte m alio llal u llits ) of bios~l lt ht't i t' hu man ~n)\'1 h hormone. T Ill' t1 nl~ wa.s inj' 't.1t'(I, 011 Sl,'!l
-
AIHI._
1w.E il'-1 "'C!lCNSllf
n "9 h
0
<2 <2
34 10
1
J
55
92
27
27
_
o-wth M_ _ " , 12 .., ,.11.wI.., 1111...
4 ~ 6 J 8 SoIR\.w. CONCf"ITlA l1ONl""""""";
Q
10
II
11
75
74
24
20
28
28
19
14
12 12
10
84 37
"
23
31
20
8
a. Is there informat ion ill l"t'Sl,' data, ~lt'am"(l From graphical llllalysis. 10 SUAAt's l wln-thr-r ab sorpnon or d ispositio n of gn )\\1h ho m lollt' rute-linuts tilt' terminal de. d im'? Brit·lI), d iM-·nss. II. \l allYp n ueiu... Kin 'lI sllIK'uliUlI'llllslynr intramuscula rly a n ' partially d{'g mdt 'tl wi thin Illt· lylIlp ha lit· syste lll bcfon- ft'ad lillg tilt' S~1i h' lll i<: ctreulu tion. C a lt11la te tilt' n-lanvt' hioavu i1ilbility of lilt' dmg aftt'r Sot' . inject ion inlo lilt' Illigli (ft,latiw to ahd olllt"n ). c. T"t' dearmlt't' o f gnJ\\1h honnouc hits been rt1x lr1t'tl in the literatun- 10 a\"{'m~(' about .5 I Jh r. Houghly es tima te tilt' hioil\1ub hility o f tln- dmg fnlll)\\i llg alxlominal s.c. illjt"(1io ll.
4'
CHAPTH 4
;,
I'l ll 'Il~ I t'lhyllll alllll id(' ( I' F. ~ I A ) is Ont' of til(' majo r me-tabolite-s of t ln- anlit'p ilt'plk (In l!!: prtnudom-. As part o f il p r ogr am to ,lSSl'SS the potential use of PEM:\. as an autk-pileptic tim!!: ilst'lL its phannacokine-ncs wert ' stud ied foll(l\\i n~ L\'. and oral adnunistrut lon of :Jon Ill)'!;. Table 4-6 b"l ow lists till' resultan t plasma concentration s in om' suhjt"(1. Also . " I'l- o f till' i.v. doSt" wa.s recovered i llllri1lt' u n ('h'Ul~t,(1.
III' at HMA
eo..c
T.It•• 4-4. PI••_
tI••• f.II_I.,
to .. s.ltl~
on
TWf(lY] , ~
F'Iom'la conc enlrahon
(mg/ll
14 7
o c!
·~""""P'>
O"d ~<"""
...
"""'010 .... 8 272,276 IQ83
0$
007
12 6 24
11,0
I
0-1 a".I. 1
1$
4
6
I.trwtt•• at
10
16
500
J2
24
48
QO 82 7 Q 66 6 2 46 32 23 1 2 3.8 4 2 4 6 8 1 5 8 5. 1 4 I 3 0 2 3 1,3
~.......,.<J~tp[ lMIa1w<:o'Qlatd-.our.cn-_
C"" Pto-
a , From a sl'lIIilogarillullk plol of 111l' p lasma concentrations. estimate till' ehmtnanon hal f-lift· of I' E~ l:\ in lilt· subje-ct . II. Cal{'nlah' tilt' total Av e f()lIo\\ill ~ i.v. and oral administration, c. F ro m tlu- i.v. datu, ('st imalt' Ilu- dt'amm'(' and VO ! U Il l(' o f di slrihutioll of P E ~ I A , d . Cak'ulah ' till' ora l hit);l\"ailahility o f lIlt' dm)?;. e. Cak-ulatt' tlu- n-ual dt'ar.lIll,(' . ,"i. Umdam l ("/ til. (Howbud . ~ I .. Epstein. \ \ '.. and R i {'~t'lman , S.: Ahsorption kinetics o f ).!;rist'o ful\i n in man . J. Phu rm. Sci...57:WH-9S9. 1968 ) ga\'t· grtscofulvtu om lly, 0.5 g: o f a mk'rtllliz("l.1 d mg: fo rmulation and . on anotln-r occ asion intr.t\'('nously. ]lX) 1Il~, III volunte-ers. T I](' ph..ma concentra tkm-tlnu- data ohtaim-d in mn - sllhjt"(1 art' W\'('l1 in T able -t-; lx-low,
T.ltl.4-7. eon rm
""'""
0
" "
OQ8 000 0 80
o
0 4 OQS
'" '"
G<,~""~ Conce
Img/tt
, , , ,
0
11'01
00'
'OJ
r
,. • " " 0"" " 0 . 8 035 OJ'
" "
.. 0 "
000 I OS 090 0 85 080 050
Frmn appmpriatt' plots and cak'ulations, what can lit, {,mdlltlt"l.l [n un tl ll' St,' data with n 'slx'{1 10 : a, Halt· tlf ahslIIvl ioll of griSt"llfuhin with tiuu- 011 orul administrutiou ill this ind hidllal? II, ( ;olllplt,!t·!lt,SS of ahStlrptio n? 9 . l\usl l'llhalldt 'r r-t al. ( 19• .'5) measured plasma phcnytom coucentruttous ufh-r tilt, ad lIl illi ~t ration of St lllium pl J('I\~1 n in inl r.UlluSt.·lIlarly (5(XI 111~) and inlmn 'llollsly (2.'50 lll ~) . Tln- :1\'(·r.I)?;t' data obtahu-d ill 12 Sllhjl'<.1S. each o f \,1IOm rt"('('i\'('{llxJth trcat nn-uts. art' lislt'(l ill Tahl" -t...s'
,.ltl.4-a.1MI"1 Pb"""~",,,~ Conce<>MO'oOf'l
Img/lf
"'""
1~IrO"'lI1(:uIoI~M~
""'W«to
..
He
~
JO
e
~ 0 ...' "
3J
38
ce 08
JQ
H ."Io:G:o.<"',JP
oo.'.,O"d~~oIo"""",.<J~~
'0--0"'\l/l
.
, • e • n " " , o 3. " 0"88 oa " " ,. s a " " " " n... 0
... DG 1liod"-,l"' M >u,.. we . O"d . ..... IB u~'>O. 1075 0.. F'Ion-o
F~.l~.Pooo-
~w
""
oa
......
a. Estimale tl.t' hiflil\"aila bilil)"o f plll'll )'to in From till' i.lII. site h;l<;t'(1u n an-a compart ~T1 S .
h . From an apprupriah' plot of till' data, couuueut 0 11 lilt' pml''S.~ Iilll itin ~ Ilu- dechue of Iht' p l ;l~lIIa pllt'II~1oill l'()lIl'('lItmt ion fol lo\\i ll~ i.m, udnuuisfr ation. c. T Ilt' authors analyt.l.'ll tilt' p lasma conccntranon-tunc dat a and found that. folJ( "'i ll~ LIIl . administratkur, 2.1% of till' do St, was ahsur l....'(1wi thin tln- first hour . und rln-n -. after absor ption wa.~ much slmn-r. Tln- curuulatm- absorpnou dat a an' shown in T ahle -1-9 . Arte r th e rapid ahsorptioll in tilt' first hour , is Iht' j,lIIN't IIlt'nl absorption 1....-tter charact e rized by a zcro-onk-r or a first-order pn K:t'ss?
,.ltle 4-9.
"
P.,..cenl <:J bioa.o,loble dfug c bscebed h-oml.m, ~,'"
23
40
80
Q()
Section II
THERAPEUTIC
REG I MENS
I' L
5
THERAPEUTIC RESPONSE AND TOX ICITY
OBJl(TIVIS The reode WIll be able k) : 1. Explain why elfecr [desired cenh'allOf'l thon with
Of
roxie) 01 a drug is often bettef
cceeoed with plo~ con-
dose.
2. Define the terms: graded response, all-or-none response, rhetopeulK: ccoceoncnce range, Ulilily CUM!, and tolerance .
3. list !he 10 nge of plasma cceceoscucos ossocc'ed with lheroJ:')' fa cny ollhe drugs given in Tobie 5-2
4 Deccss bliefly situations in which poor plasma drug ccoceoececo-resccese relatioru.h,ps ore likely to occur
bfiefly why modality of odmini.wo rion of a given doily dose con affect therapeutIC outcome.
5. hplain
TI l(> rational d(osign of SOI[ I' a nd (·flkliLiolis d O'i- 1. One co nsiderano n includes t!lCIS(' fadon; thai fd att' to both dlil'at" , and s...'lft't)' of the dmg. that is. its phannal'Utlplamks and tU\k(llo~~)', Anotlll't l'u llsit!e t'a tion is 1111\\' th e hody act s Ull the drug and its dOs,;I~t' fo nu . Ihe essence of pharmacckmcncs . A thinl n )lJsit!emt inn is that o f tilt' clin ical state o f th e !),;t1 it'lll and his or her tnl al tllt' mpt'u tit' rt~ lllt'n . A fourth eatt~of)' includes all otlu-r Factors sllt'h us gt'lwtk differences . tolerance . and d nlg tutcn«..1:itllls. All of tilt'S(' dt'll' n ninanh an' , uf course. lnn-rrelan-d alltl in terdept-'nl!t·lI1. 1l<:1.... lgl· n~ lIlt'llS an ' ( !t'S i ~ l t-d to produe- a therapeutic object ive . TIlls objt'cti\'{' 1I 1i1)' lit., ad li('\'t"t! by S1lriOUS modaltnes of d mv;admi ni stmti o n, t'xtl' mling fro m a sinWt' occa-..iullal dose 10 co ntinuous and constant inp ut. An exampl e o f tilt' for mer is the list" o f a...p irin 10 In'al uu 11l'(.-a.siu llal lwmLld ll'; til(' conunuous is , infus ion of le-pann to maintain a tIl'siR't1 dt ogn't' o f a nt i t't "'I~ ll at ion is all ('x3mp lt, o f tilt' latter . ~I o n' commonly, dru gs an' admtnisleR'll rt'IIt.'ah'tll)' ill dlscn-te doses . Tlw fR't"II'III'y am i duration Sll ry with the- l'tllld ilio n Ilt.'ing treated. Sonw d n 'hry;. 1II't'. admintste-n-d R']ati\,t.'Iy infR'tl'lt'utl)" prtX lll<.in~ larv;t.' IIlIl'Illations ill Ihl' plasma conccntranon. !tt ' il'it.lIlS fur thi s approach incl ude tilt' dt,\"(.']uPIIlt.·"1 of tolerance to th t.' d ntJ!: an ti llit' 1U't't1 to produce hi~h concentratio ns fO f sho rt pe-riods of nme. ,1-\ OI"(' U fS in some lllllillint ic am i anticance r cln-ruotberapu-s. In ot her situations, mai n-
THERAPWTIC RE5PONSE AND TOX!C1fV
54
tenance of a "-·b lively constaut concent rution of dmg is 1ll"('1lt"(1. In all cases , attempts an'
111,1(1., to minimize uudesirable and toxic effect s am i pn-veut ine fTt"t:tin " therapy. Evuh-nce- t'xisls tim! n 'sptllls(' is often la-tter co m-lau-dwith plasma concentranou than \\; 111 d uS(' 'I(Jm iuis ll'rt'tl. A(:(:(J nlill ~ly. it would S('{' 1Il to he must appmpriah' III apr l>' phar macokim-ti c principles to the desi).,lJI of dosa gt· regtmeus. 11111s. ~i\'t' n ph annat1lkirwt ic da ta f(JlI O\\in~ a si ll~l t' d"o;(', tlu- plusma conceutrunon O f amount of drug i ll tilt' hod): fllll()\\ill~ any dmill ~ sd ll' lI11' can IH.' estimated. Ultillllltdy. however. lilt" value of a d()~g(' rt '~IIl('n ruu st 1)(· ,l-ss('s"'t't:) hy tln- therapeutic and to xic n 'slxlIN'S p"-)(III('('(I. Plumnucokiue-tlcs fadlila h-s til t' achievemeut of an appropriate dos,:l~t, rt" lIlt'll and _'it'I"\'('S as a useful !lIt'1II1S of (,vllluat i ll ~ t'xbti ll~ t!USilJ.:C n.-WIllI'IiS. III Illis ehapn-r. \1uiOIlS r-k-ment s of tilt' l"tlll<."t'lIlrution- rt'spOll'it' rt·laliullShip an- ('Xplcn-d. Prilld pll's fur att ai ning and lIlilinl ainin~ a therapeutic It,\"(,1of dmg in tilt' bodv und ist.'usst't l ill lilt" subsequent h-\u chapters of Ihis seceton.
RESPONSE AND CONCENTRATION Ih 'sp..lIlM' Illay ht, as n lWlt' ax a g"'lwml fl't'hug of Imp r ove-uu-nt or 'L~ p rt"'t.'iM' 'L~ a l"I\\"t' ring of tln- di ,Lsto lie h luod p ress urt' hy 30 IIUIl I lg. lnfo n uunon rdalin~ conceutrunou 10 rt'Slltlll'it' is oht ,ullt"'t l at Ihn-e h-vels: 1'1 r;ll m experinwnts, nntmal st ndu-s . and ill\"t's tig:atiolls in hiuuun volun teers and pal it'nls. TIl(' last \('\-...1 is II.... !lIml releva nt to human dmg: Ilw mp>- but. unfortunatr-lv. onl>' Iimilt "f.1 lnfor. mali! III is 01'11'11 uh la inah lt, !lt' n ' a"ulil Ih.., nature of the dmJ.:- rt·(-'l 'ptor tntemcncn. /II l:itm cxp -rtnu-n ts. wh id l indmk' studn-s o f the act ion of dmgs Oil ('Il7.pll(·S, receptors. mien.. nrgallisllls. ami isolat r-d tiseues ami organs, st' l"\"(' this purpose Ix-st . lI oWt'\"(" , in iM,I.ding tht' variah ]"s , lIlany of lilt" comple-x Inte-rn-lationships that ('xisl in 1:1..,., are t1t'st n ~l 'tl. Animal Silltli('s hritlJ.:(' much of tjn- J.:ap h..'I\\'("'t'1I in t:it m t'\pt'rillwlltation and hu man tnves tiJ.:alioll. Studies ill animals introduce bot h lilt' variahh- ti me, with all that it connotes. and
Thercpecnc WIndow
Ab>o<""",
Sod. ""'" To,,,,Jy Coeceeeceoo-se scoese ,elohon!>h t~
MeIoOOIism
Di~lIlburlQ/'l
EJ«:rehon
Dosage Regimen
O IH( ~ l...clorS
Sl A't QI PArtNl
Age. weoghl Cood "l()ll be,,'9 lleoted h,~tenee
01 orner d.seose $JOIe~
Nv"h,pIe d"J9 lhe
~~e 01 reg'men Compliance 01 potoenl
Rou1te 01 odm iniSIIOf.on Dosage fo.-m Toe-crce-deperoeoce I't>ormocogeneliu-odl<)$Y"C'osy [)-ug Inlefoct>on~
COO'
OWTH 5
55
till' elements of abscrpuou a mi tlispos ition ;1..s \\'1·11 ;L<; till' fl"t'1.II"lt·k t.'olltm l li)'litt'IIIS tllilt operate- tn mai ntain homeo stasis. Animal st udi es a n ' nfh 'n most IISt'fu l for l."\1J uatin~ tilt" p lmnll"nlln¢ c lipt '1.1nllll o f adhi ty of u pOb'nti,,1 tlu -rapcutie a~l'lIt a nd for dt'tl'rlll ini ll~ ;L\I'It'1.1S of its to '\;il'il)" pmfill'. IrT(·spt 't1i\1.· of tilt' It,\·d of information, I.tJ\\·I.-,\1.'r, th e concluston is the sante: A rt-latkmship, allholl ~h sometimes complex. e xists 1I<-'f',\1.'<"11 the t'UlI(.'t'IItrutiou of ;It1h1.' a~l'llt ut tilt, sitt' of III(',l<;un'lll t'nl and tilt" n 'S!'ltlllSt', TIlt" 1ll'ljOril)' o f d n lgs list'll c1inlt,;J I)' ad n '\T rsihly ill t ha t tilt' e lTe(1 ts u '\"t'TSt'l 1 UpO Il n'lludll~ conceut rattou ill tilt' silt· o f m.1iu n. ~1;1II)' n'S!)flllSl'S produced arc j!,mdr d , S( ) called ht '1.'illls(' the Illagn itud t, of tilt' n 'spelJl''l' ran 1'It· <;(';llt1: 1Of g radt"ll. An examph- of a ).,rnlllt'( l n.'s po llo;e, St.fM11 ill Fi~. 5- 1. is tln- illlpnJ\'('lIlt'nl of pulmonary fun l1itJII produced hy tluhnmdll'lllibiur IN h ufalilw . aftt'r its s.c . admi nislratioll . TIl(' inll' n\ily of the n '!ipo llse varies with tilt' tl m ~ cmu-ent rution ill pbsma. Ma TI)" otllt' f phannacolog tc and to xic rcs peJlls('s tin 1I0t occur O il a cont in uous I"l'iis; theS(' au' knowu us ({u(w lnl Of nll..o r- ,ulIIt' fCSPOII"iCS. A ll O" \;OIlS bill extre me l·x.a mp lt, i ~ death. :\lIol lw r h till' supp u 'ssio ll of all arrh)1 111I1ia. TIlt' arrt.)1111Iliil either ts or is nnt sUp p u 's"l'(I. SOllwtilllt"S, a limil ts St·t nil a gm dl'1l rt' SpOIiSl' ht'l o w which an t·lTl'(1 is said not 10 OlXIII" dini mlly. For exam ple. a poh'nliaIl)' toxic (·llt'1.1 of alltihHlt·rknsi\ 't.. therapy is an t',l('t'ssin' It J\\'t' rin ~ n f hltlllli pTt'S.'iIlTt·. 111t' I (M·t'ri n ~ of h ltll'lll pn·sSllrt· pnxlul,('l l h) ' th l' antih)] 'It,rtt'lIsh"t' a~t' ll t s is it ~radt '(l response, hili h)]x .te nsfve Imidt)" is said to Ott 11f u nl)' if l ilt' hh'lll pU'ssu rt' falls In IIlll ItM' a \1J IIl'. Hen- the chmcal I'ntllx)int is all-or-uone, bill ti lt' phafm 'tl'tllo¢l' n 'sl)fIllS(' is ~Tildt'll. Ht't llnl illg 10 tt·rlmtali nt'. F ig. ;>-) is a plot o f tlu- fof( 't."ll expi r atory volume in I Sl't.,(lIltl. a me-asure o f pIlIIllOIl;II.,: function. a~itj llsl pia.s ma concent rutiou. 111(' plot is dmmt'!t'ristk of most graded ft'Jij'ltlllSl' curv e-s. A ucu rly lillt'''f n ·l;ttionsh ip 1'It'I\\,('1'1I t ht~ intt' lI:'iity of rr-. SpOilS(' ami tilt' concentration al ItJ\~' coucent r attons and " It'ml t'ltl')' to n';~ h a lu .L\inml n'sl'ltllls(' ;t! high concent rations 'In" a ppan'IlL Unlike a gr aded n·spoIlSl~ . the- co m-lattonlx-tween a flualltill n 'sl'ltlllSt' and enncentru tion is t·.\p lo n'll h)' I'xam i nill ~ t he fn'q'lI'P1oJ of tlu- event with conceut r anon. 111i:'i is iIlust Tilh "ll in F ig. 5-2 II p lot of fn"(llU'"l'''' of ti lt' supp n-ssion of ventricular errhyt hmias us II Function o f the plasma comvntrauon o f till' untiarrhyt hmie il~t'll l pn:lt'~ti n;u ll i d(·, III IIltr.;1 palit'lI1s
"y
3.5
•
• ~
E
=_ 0
. '1 11:. 5-1. n il'" n..-_ f"'.....1 •.~pi . 011"1)' .... >1""... in I .....'('n.1 (H':l' l)
•
j n (· r,·a~ .. t lUl l<..·nlr
• • •
3.25
". ~ _o c0
.~
:rl
3
•
'"-'' .:l
~c ~
"
of
.-
2.75
• 2.5 0
2
4
6
on.. an
pla u"a
1, ..;1 tin l<.. in
10 p.tl it-"b I(i'~n O, ~ "'II: of ft·rhu. l..Ji,..· "ull<~,"'.r"" " I'Iy. n ..· i"'I"'''''' nwnl in pulm" nary {uIIl·ti un In(." ....... ,,; 110 pl. ,m a ('t.nt"· ulraU,,.. h"l "l't........ I" "'1'1 _ ... a 1i",;Ii..Jo( ' ·aluI". l ll ...l nown r on ( ),,,I.. rt,,,i• . B.• 6 ......1. I' .. K< C .M,J., ", ..I V.... 6"''''1. C.).: t1 rm ...""indi<'-p" "r. m....... lynami<· " It4i"1t or 1.-""'1". ln..· h.." ..d .... lilal i.. . . llo ma. elm. PI,.. rm . c,,1. Tl w r .• -IfJ A6 !1- 4';'S . 1\1116.)
•
>:.
wnh Ih .. 11
B
Plasma Terbutaline
Concentration (JJ.QIl)
10
12
THE PA!'E UTIC PE5I'()NSf AND TOKIC ITY
56
100 " l.it. ~2 . n ..· (1"K~'n l r;i1i"l\ " f pnJl·;uII,,"'il lt· ' ' ld n mj'.....1 in "",r :11 0 1 n......1111'1... ulo'ail 1 fn " n zYl ["'Ii/- nh n '(,...i' ; Il l( rhi' ,In'lt fu r lh. - ! " ,,,I · llIo''' 1 ,J ...m li...· ..rrt,~dlrn i.L. , n ..· rn"I' ,, · rK~·. t'l1'"1"' " p,-n , ·nl .. f 110" n 'llnl ~'r flf 1'L..",,;o \.;1m· I,lt~ ilh ",,-I' il-l, .. ...·n" " n ·"I ....' ..'" (' >m ,L.I. .. ....it l, .·IT....i i\<· ' '',·rolJ.~'. illl...• "'illo (';><-h inl'-"',;I,t "f iTIlTl·..' illl{,,,,,,,,,,·utr.lli,," n ..· 'Oil",· ..I..".. '-;0(·1, I , ,, ·(.-n t" ,h., "",,,1,, ,( " f "''''1'1.... "ith;" ,10, ' n', ' 1 1" ... ,uI.. ...'1I1 lIu " r.II1l:<' {I "'II: (1",,,,111 . - 4,3 11 M ). (Frn", " ,.\\.,.... 1'. J.: '" r1...n".... .I.'l:,' ..,..I tI..· Furun ': Pr..I.k-m. in ~-. Edih..1 by <:T. Ol d.. ;1,..1(;,11 . ..\"............ ":"JJ't·r. &.....1. IY7.1 \", ~ _
101 79
"I.....
n ,,·r...
37 r-
807 ~
r
80 1 ~6
60
40
~
.1· 1'11_ ~U
20
o
In 4~ 11-10 12-16 2-4 6-8 10-12 > 16 Plasma Prccainamide Concentration
<2
(mgIL)
rlu- a rrll) 11 I1n iR~ art '
.~ Il pp rt's<;( 't l at {'OIl{'t'lltrtlliflll\ of 2 III '" mJiL. Il uwt'\'('r, tllis ht'lies
tilt'
entin- pk-tu n -.
THERAPEUTIC PLASMA CONCENTRATION RANGE Fi~lIn' .')....,'] shuws tilt, pt 'n.'t'nt u f IhclS('()
CHAPTU 5
57
Therapeutk Window Let us expand philllsllphil'i.lly 0 11 thts l'()n('t'pt of \\l-'i~htin~ dt"1.'!opt'1l for p r ocainamide lilt' iuforr uat um in F i~. 5-.'3. "d di ll~ Itn 'Jl.'rsc.'J\sithi t)' and a.ssign ing values 10 tilt' reSPOHst'S al'(.1mli ng 10 OIlT 1'Jl.'st judglllt'lll . Figurt' 5--1 sho,"\" lilt' prnhabilili('s of til(' reSI'Jl.J!lSt's. p lus that of I I~l)( ' rwll s i l hi ly, each wt'i~h ted b)· a j U
20
o
o
4 B 10 Plasma ProcainamideConcentration (mgll)
H K. .5-.1. Sd"'n~ttil' n ·l'n ....·nl ~ti.. n uf Ihl' fn "l" l"K.)· of 1rM,ITI'dr. 'l"IIM·IllJl:'·. ..IT.'l'lr.,· Ih" r"P:", m in... , itlt· ,·IT...1... lIllill.lIui;o.l it-nt. n'l1-Mu l/: " 'n'M" I,,\I.,I~· . • ",1 - IIM'ro' !,,''' Ii<' ~·IT''l1r.1·11n.' · i t" lI.i, .! m~ II..• In 'al l1" '1I1 rrl l~dll"i ",-•. n ,,·r ,lk toIT''l1i....''•.,.. iJ .1,Alr.....I ..rl lil r..,; I~, .... " M' .!iIT,·n..,,:.. In lh., (n "I"'·' K) · I.' ·""1'Il .. ff''l'l I", tl" 'rdl':" "'K!I.."Ic~,ff,'l'l'; II... t ht' r.pt.' ufK't·fft'l1r. ...1WU(C'o l" f('lJ lillt' ) .. f pm.:>lin..mid. , ...·;1(·1..... ~ l,,·,,~ .. t 'I mWI. (I "' ~ . - -I,311- \ I J. (/" I.' I'« 'l1 fn >ll l ll.., ,I." .. of K,K.1,·W....·r . J.: I.. 111
ror
or..
rl....
c. n.
~') . )
"
CHAl'TEIl 5
t1l'\a~t · ~ 1 1l'w " witl,' r.t ll~(· u f l'C Ill("·lI t ral i(lIl.~. I('ad i ll~ rme- 10 ques nou S "U"ill~ tll\ id ly lIIi ~ht l il r.l It "t l ll m lll ~1. all tilt"
if sdt'l1it lll uf Il
linn 0 11
Itl\idt} mus t come fnnn th e- patit-nl wh o . for OIl(" rt'a\llll u r al1othN .. ('xh ihih lo\icit)-· hll'l"dU"t· Ih t· (InlR ('IJll'("l' n l rd tlo fl is (,\I't'SSI\'t' or \\110 !la' an u n usual " "!ipon....• a l a 11M' t'l IIl('l 'lit m h! In .
Desired Effect
+1
n Ullioty Serious Toxicity
Curve
Minor Toxicity
- 1
0.1
03
1.0 3 10 Plasma Drug Concentration (mgll)
30
100
. '111:- 5-f. 5.-1.......1 da.althm of Ihr ,",lp;hlnl pmb.bilib... of rnpon '" Wnul dw.o paa..... ~ n1 rabon o f • •I~ n...prnhooh il,t1 from Fill: 5-J (plut . h)T'Ol:ktnl h)l'"V 'lIIttvity ... amnn) . ... ~t...J by ,.... loll<-. in lt L..1" "" ',...I ..ffrct. L hYl""""'ft.Qlivity. -5, minor lulU<'1ty. - t ...nou. tnUdty, - 5 . ~ a1K"bnoioc . um of I.... --1,;"1 1 pmb.. hiht..,. ,. lhe utility CU~ (cdo~ line). ""CONIn'; 10 Ihi. K hellMl. I.... hl.v-.I ...."l'II(hIed. I'n >h.chthty o r Ihrn[""ul k: , uaT" Ott"\In al II mw'L and c.'O T"KTnirationl ....l.- 2 mWL and .lxM. 12 mWL ..... pnlt'nl l:.llly mo rt'" harmful du " bt'nt'flcial
r Or til<' lll;ljOrit~' u f 1l;llit'llh , klluwl ("dgt· uf ;l dm ~' s IIlt' mpt 'ul il- p l'L\m" l'Ulll,'n fratiu n aml p!J'lfl llat1, killt'ti('S ..hould h-ad to a ilion' rapid ('sIOlhlisllll lt'llt of a saft' and t'lli. (',WiOll' c1", a),(t· rt·W"WIl. Il nwI"'''''r, ti lt' na rrrever Ihis r;IIII-:I', IIII' mon- difficult is li lt" m.uun-namr- uf \"allU', wuhm it. 111(' p la.\ITl
CHAPTH 5
'9
THERAPEutIC RESPON5t: AND TOXICITY
furin. is all example of till' foruwr ; the- Olo lo"id ty l'iIllSt... 1h)' th e anlih iotk ~t' n t a lll i d n is iUl example of lhl' latter . DistiTld iOIl also Ill... -ds 10 ht· made hetweeu the Stl"t.·plll'SS o f a concentrutkm- re sponsc t-urve andtln- width o f a tlu-mpeutic wt udow, Th is point is illustrate.. . ! SChl'llliltil'itlly in Fi~. 5-5. Fi ~lrl' ,5-.'5:\ shows a t1n l~ wi th 11 \,ide therapeutic \\im!fJ'w , 111l' \\idl' window OI"t.'tITS tlesp ill' slt'(·p concx-ntranon- res ponse- 1'lIn '('5 for both efficacy and toxicity . li en ' toxid ly OI"t.'IITS ,II lUIII'l·nt r.llio!lS wt'll uh"\"l· those TIt'("t.II...1 to achi eve maximum dl' sin...1d Iet:t , 'nit" normal sl mh'~' wlmld Ill' III t'llsu n ' that all patients n-cefve a tluS', 111is narTO\\1lI'SS ariM'S hI" l'ilUSt' Iht' n 'spoll."t· t-urves IM'rlap wellbe low Illaxima l effiCill')'. so that it is d iflk 'u lt to find pla.s lllill·om'(·"l r:ltiol s Ihat produo- t·ffil'ill'">, without SOllie tI~n"t" of limitill,glo"idly, It is In ht· stn 'sst'l ! tlcu si,,~n i fiednl intt' rilltlisitl uill \"ariability Illil" oc cur in hot h rlul.ffil'ill'y a lltl tm id ty n.·SptlllS(· curves . It'a
Acetozolom,de Am,l:ocin Am,tnptyline Ccrbceczeprre
DnI,..... Thel.. PI...... c.__......_. U_.11y
1n..-py
DISt-'So! / CQf\OIICN
1"")111
Oooccec
10-30 11-25"
GtOf!'l'l'lll9Ol'.-e infOClOon Dep,,:!won Epilepsy Organ tronspionlOhon DepteuOon Codoc dysfuncbon Coooc dysfUOCf'on Epolepsy Gtom-negorl.-e mlecbon Ventricular olfhythmios Noon,e ond recUfrenr depleMOOfl Endogenous dep<euiOn EpolepSy Epilepsy Venrriculor OlfhythmlOS Venrr iculo, OlfhyrhmlOS
C~bspollne
Desiprom'ne D'9'lox,n Digoxm Elhow.. mode GenlOmicm tdccc.oe ltlh'um Nortr,ptyline flhenobolb<101 Pheny!oin P'OCO'f'O:Jm,de Propranolol Solocyloc Acid
~~ Ac sand
pa,ns onnllr,s
~heu molQ;d
Rheumo',e !eve< Asr+.mo and ehrooie obsrruclo-,e a,"""OY d.secses
Theophyll'ne
"""'"
GrOm-negollVl? mfecrOOfl
Tobro'¥in Wo.folin Volproic Acid Voncomyc m
Throm~boIic d, seo~s
Epilepsy Penic,II'll'fesiSlQnl jnfedOOfl
" 1\-"'; .. ......., 0;;.,. a ')0..." ,.........",
""""*"".. <0"<:_
• I\n<"O d>'vg ploA ~ ' ~ ..,.,.; WNj-.
" ~ _>hoIcl< ~
• ooq. ........... / ' o ~ """,......::l,..........,.., ... ~ a.:...
0!2-o25~
1. .'0'1
50-150
002-02 20-100 100--300 250--400 &-,0
0 43-0 QO 17-51 o 13-034 045 0013-0026 0 ,<XX:la-0oo3 lS0-540 7-21 4-25 a 4-1 4~ 02-06 40- 120 3G-60 3G-60 17-34 OOa-0S 150-750 750-2200 1800-3<XX:l 33-100
5-10 4- 12" 1-4 40- 100 5-15'
28-55 35-120 3-13 2S0--0QO 3 3-10
4- 12 o 15-04° 012<' 001-002 o <XXl6-O 002 25-75 4-12"
2-<> 005-015 10--30 1~20 1~20
'-8
CHAPTfR5
60
ommendr-d the rapeutk- wim!o"v, Thi s "'iml"w doe s St ' I'\ "t' it S a IlSt,rlll ~\Iidl' . ticularly in the ahst'lIl'(' of mlditional Informa tion about til(' indi\i tlual.
hOWt'\'(>f,
par-
n.".pe
.111: ' ~'
A
nit" " i ,IlI, " f .. t1...r.'l't·Ulk 100
" ·imlco.... d"IWntb on the d"lI:ff"t' of
."'-rt.s' of the· ••ffir.....,..( 1)I;o<'~ lillt",) .",..1 !,niOl)' «'" I",n .J
"'''I'''''''' (..,....... A _ nIt· tl lt"T>I.!"" !i<-
75
" 'ir"IlJW b h""Il-d) ill wKIl· l ll"$(>il" shot1'
,/
If
li"..s).uu." lr..i,,"-
I
I
('OIl (-. ' Il ! n. ! i o ll · r(" p
Id l. .. ffit"lll' - aI,,1 lU~Kit:v. ;to lh" n' i. \i rt u••IJ:. 110 .." ...up 1..-t\oo.,'nI th.. ".., "'''I''''''' ' (.......... B. Th' t1...r~'1'Ii< ..i ... I<_ (st-I<.JI i. lI..m""· I..ot:>Ill..•.. f .. h;¢. do"",... of ,,, .-lap h..ho...· 11 .. f.
ge,..., . .....1 l..:ridt)'
II", "''''1'''''''' (..,
50
I
.,." II"..,,",, 1",,1. lUl'
"...:Ill",,·.
25
o 0.1
)
/ t 10 t OO reoo Plasma Drug Concentration (LOll Scale)
10000
B 100
~ ~ ~
- 8o
~
~
~a:
!l E
:. Q.
75
~
50
E .~
~
:E
25
o 0.1
1 10 100 1000 Plasma Drug Concentration (Log Scale)
10000
., corn-late than dosa)?;t" This II1ml 1)(' true follo\\in~ a single dose of d r ug. stnce with dose alone 110 account is taken of tune. It may also he true for conttuuous dmg administra tion hut for i t difTt'n '1I1 n-ason . TI ll' objl"(1 i\"t' of most dmg tlw rap)' is to mai nt ain a stable t1lt'rdpt'u tic f{'spo nse . usu ally by lIl ai n t:tin i ll~ all (·fT('(1in ' plasma concent ratio n. Figure 1--6 (Chap. I. p. 6) sho>\\'s tin' relationship lx-two-n the steady-state plasma concentration and the rate of ad nnmstra tiou of plu-nytom. ('xpn'ssed as the diUl)' dose pt' f ki l ~ram o f bod y we ight. "111Cn' an ' larg{' inle rlndi' i d ual dl....-iations in till' plasma concentration at all)' dosing mil'; in till ' patiellt cohort stud ied . tilt' plasma concent ration ran~('i l Imm JI('ar l)' () to .50 mWl. when the dosiJl ~ r ate is 6 lllWddy/k!!: o f hot ly wd!!:t.l. Had 110 correction bee n made for body weight. til!' dt"\;a liolls wo uld han' h('('11 ("\'('11 ~n'ah'r . III contrast, plasma concentration ccrn-lan- s n -asonablv well '\ilh effect . Thus. seiz ures art" usually effectively controlled at concent nations hdw('('n 10 an ti 20 m!ifl.; sidt' t'lTt'li s O("(1 1r with inl're asing frt'tlue nl')' and severity as tilt' pt Lsma coucentrunon exce-eds 20 mWl.. as sho....-n ill FiF;. 5--6. The fin l si?:JI o f toxici ty is usually Ilysta~m ll.s . whkl. apr~.'ars above a concent r ation of approximately 20 mWl.; gait ataxia usually ap pt'an wi t h a cencentratum app roach i ll~ 30 mw'l.. am i pRllonged drowst m-ss am llt"i hargy lIIay bt' seen at con centrano ns in exce ss of 40 IllWL For phe-nvt oln , plasma concentration is a be rter correlate than dose duri ng d m mk ad ministration b{'l'au S(' ph arm al'tlkilll'tit.'S is til(' majo r source of va riubility ht,ty,'('t'1I dose am i rt'Splllls('. Fo r other d m gs, s1I(·1I as umpictlhn. pbarmacoknu-ric V'd.riahilit)' within tht' patit'llt population is n' lati\l'ly small, ami variahility in the concentranon-response cu rve is la~l" In such cases. plasma concentration is no be tter a correlate ....tth rt's rxlllSC than dose am i int!t'{'(l may 1)(' "UfS(' if. for exa mple. met abolite s con tribute to act ivity and toxicity (S('t' be-low, Addi tional C.ollsidl' r.tlio ns).
ADDITIONAl CONSIDERATIONS D('spilt, the appeal. meas urement of plasma concent ration is rt'latin·ly UIl ( 'O mJllO I\ in d inleal practice (St'( , Coucentruttou vtonnortng. C hap. 18). Tilt' major rcusou is the ....;dt· margin of S
MenIal Changes
• •• •••••• •
nil:. 5-6. 11M, rit;.. ,,( tI.., "nl'..... rd ( ,If,,<-{. of pI...n~-{"jn 1f)("R'1I.. ~ In p"'P',rtl"" I" iii (. .. ,.
....• ... ..:...:..
Nystagmus • ••••• ••
•
o 20 40 60 Plateau Plasma Phenytoin Concentration (mgll)
and Md )oy,.. ll, f .: 1 ),r'It'Il) II,~,""nl(>i n Illt ,t;a!>,,· It.. " . I>h,,1 1o·....Is, ;11,,1 tnu(ity. An"', :-..."n.... 1l :6H----64,). 196-1 . Cop:o'rill:ht 196-1, Am..ric-lIll M ...lIt..I A-."i",li.." . )
.2
CH....PTU 5
Active Metabolites VillI's>; ..eth l' Illt'talxllih' s an ' ,,1<;(1 rm-asun-d. poo r l"Om ·I'lt in ll:'l liMy ('xis!. For example, Il;L\("() em its pl il\lIIil cnucentration, al p n-nolol Is mo re act ive as a P.hloc:kt·f wln-u J,;\'t' ll as iI
s ill~lc'lIral tlOSt· th a n wlwlI ad lllinisle fl't ! inl mn ·II()IIsly.l1lis t1 n1~ is h i~l.ly clean-d
lin-f.
hy the'
and ...., in terms IIf tilt' pa rent d r ug. till' om) do St, is pnorly luoavallable. 11IJ\\'t'\l.' r,
l a~I'
a mou nts of Il1d ilho lilt·s, illdtltlill ~ an ad h '(' SI)('c:ic's, " - h}d rn~11Ipn:' Il(Jlol. a n ' fo nm't! th e «leorptlon prnt't'ss, whlch exp lains ti lt' appan'nl dist·rejlillll")'. Th e fri<-)'l'lil' anli a s("(.111lt l esamph-. Its a lll id e p rl's!i.;lIll ;«.1 i\it)' co rre lates poorl y \\i lh till" plasma concentration of p aren t drug. O nly' «tu-n tilt' cont n button of its at1 i\'I' t1t·smt'tl.ylllll't lthol ilt· is alsu ('llllsid t'rl"{! can IIst·fnl co m-la tions Ix' estahhshed . OI)WT t',,-am plt's IIf ,1t1in' Ilwt aholih's allt l III(> Implk-a tions \\;111 n 'slx'{1 10 the-ir p lmnllOico lngk n·slx lIIst· a n ' d ist.·lIsst't l in C ha p . 2 1. ~l l'l al x )l i lt' Kill(>l il's . d ll rin ~
Chirality :\I x ml 41)q- uf dm ~~ contain run - o r mon- a.~Yl n ll Jt' l rk k h ira \) l"l.'n h'n> in tjn - lIIoll'{·IIII·. F ur t'adl center, then- an- Iwo pos sihll' mirmr ilTla~l's o r enantionu-rs. the H· a nd Scfo rms . whil'h o fh 'll tlifTl' r ill their pharmacokuu-nc a nd p l.'IOnal"lKlylla m ic properties . Bt >(-,UlSl' of t1 iflil1lhy and cos t o f separation. Ihl ' majo rity of S' l ll hdil' clural dm ~s a n' lIlarlw h 'tl as rucemlc IIlh !t ln's. FaHIITt· to list' a stereospe -ci f ic(:III'mil',,1 a......ay In II W,l~IIf(' tilt' Individual t'wm iio lllt'rs can tln-n-fon- h-ad to probh-ms WIIl'II 11Itt'lllpting to co rn-late pl a.~lIla ('(111('('11 ' lralio ll wi l h n ·spo llst· full uwinj.!; ad mi nisl ratio n o f l ilt' r.ll"l·nmlt·, Even wlu-u a Sll'r't'oSllt't:ific ,l\Say is t·llIpln~ l'tl . il i\ not a lways 1 ',L~Y to kn nw !lIIW to ('(lIl1 hillt· the- I' na llt iollwr l"llll('('nt rat ion s to n -lan- III n ·spo llst· when IXltll t'n ,lIltiOTllt' TS coutrtlmte In ,1l1 i\il)', f o r exam ple, altl loll,l.!;h B·\m rfa rin is II'ss potent than S.warfa rin . it can vtill pnKIIll"l' ful l an til"lli.IWlbtioli . T h us. n ·spo nst· cannot Ix' n-lun-d sim ply In tln- SUIIJ of t he concentrations o f warfari n
enantionu-rs.
ToJeraMe and A(quired R.sistaM' TIll' t'fTl't:l i\'('lw ss of a
tln l,!.!; can di mi ni sh wnh contiuual u w. Al"lluin't l n-s tstance rk-uon-s !11t' lIillli llisht'tl st' lIsith i l)' uf a pop ulation of ci -lls ( lIlil'n xlrga llislIls, 1I111pla.SIIlS) 10 a cla-. lIlotlll'rapt'llHl' il~t' n t ; 10 It'f'dnl1' d l' no h 'S a d illlillishl 'ti pl mn mK"l llo~~ l' n'S lxlIIsh'{'lll'SS III II d m ).:. TIll' t11'~n't· o f a("lillin't! n 'sisl;llI<1' \";trit'S; ilmay Ix· compk-te-, 11l1' n'''Y n' ll( k 'ri n~ till' a~(' II I , l · . ~ .. a n an lih iol it.', iTll·fT('l1i\'(· a~aillsl ll lllienX I~llll i slTl , TIlt' d('~n '{' o f 101('fllll<1' a lso vam-s 11II1 is Ilt'\l·f("lnnp!,·h', Fur exa mple-, within day.. or weeks o fits n-pe -ated use, suhjt '(1 s run d t'\ 't'!o p a pr ofound toh-mncc but no t Inia l UIlTt'sIXJIIsi\'(' lll'SS 10 11ll' p llanna('lJlt~ C l'fTt'(1s (r-uphoria, st't l!l io ll, n -spira tOl)" (It'p n'ssio ll ) of 1II0rphilll·. T ok-rance can d t'\ ·(·lo p slow l\"; I'.).:., lolt· r.lII(1· In lilt' <1'lIlml lll' n nus S\"sh'1lI {'fTt'(1s nf 1'llI allol takt·s w'('t·k... ToINlull ' m ll(,{·. l·xpn·sst'tl l,,· a di m in ish t't l lllll'l-."l"lUl al""l Ol'{'ur 'll'uld y (t 'll'lJ, p hyl l\ is ), (M.m lim ·'lw u b r Tt·sIXJllsi\'(,!It·\\, d l'\'( ·lup s \\ilh in lIIiUllk s follt r.\i ll,!.!; n 'lx 'l ili\'(' ad minislmlio ll u f ma llY II ' pht 'l lt'thylil1l1iJ l t· . I~lx· S)lIJIXll llo lllilllt' lil's , Sill'l l ,l' i"" p rtlll' n 'lIo l, AI all~' mUlIll·nt . a ('o r rd al ioll Illi!!:hl ht' found Ix·tw('t'll Ih(' inh' nsity o f n 'slx )llst· ami l ilt' pl'lsma l "l)lll't' n!m · tion (If lilt' dnl~, b u! till' n ·lalionship \";ln l'S \\i lh liuit' ,
TIllis.
Single-Dan 11teropy 0 111' do",,' o f ;l' pi ri ll l'~ lII l)ft l'lI n ·lil'\'l· a Iw,u!;u:,Ilt' . whil'1. d lx's 1101 rt'lu m l'\'('11 wlll' lI all ihe ti m ,!.!; has IX1'/I d illlinalt'ti . Ollwr I·xalll pl(·s of t' fTl>(1i\'(' si n~I t' -( lost' IllI'ra p)' ind udt' l ilt' 11M' of iso p m h ' rt'lIo l 10 rl·lil,\ 't· a n lK'ull' a,t!lIuOIt k ult aek. l"llleh ilillt· to In 'a l a ll a("ll h' ~l)lI ly atf a('k, nil n lj..(lyl,1·ri n In n ,li('\'1' al11t!· t'p isodcs o f a ll!O na , a ll(l lIl0 T) !Iillt' lo Tt·lil'\'(· aClih ' pain . A l! h oll ~h l ilt' slx't:i fk IIlt'(·!Iallism of al'lin n i.s " flt'lI Ix xlrly UIllII' rsl( xxl, till' (lS'(·mlll·fTl'{1 is
THE RAPEUTIC ~ E SPONSE AND rooctv
CHAPTH .5
63
km)\\ll: tlu- t1m~ returns .111 out-of.. balance- phys iolo~~k S)'SIt'1Il to wit hin nonnal ho un d s. Then-after. fl"l'tlba l'k control s\'Sh 'lIls withiu the hod " mai ntain hom eostasis. Tilt" need for dm~ has now t' ntlt'(l. I II tln-se- tnstanl't·s of sin~lt'-(!l)<;("lllt'mpy, 11 correlation hdwt't'n t·rTl'(·1 and peak phl.s ma roncentrution lIlay exis t, hut I X~~ lIld tilt' peak, :my such correlation is uultkclv.
Duration Versus Intensity of Exposure Sonu- cln-motln-rap-utic a,gl'nts . t' .~ .• nu-t hot n-xate. t'"hih il peculiar n -lanons lnps 1)('lwt't'n n'spoll w am! tIm t'. TIlt' n'sl'NIllS(' ohst'r\"('tl n-lates rnon- dosdy 10 lilt' duration nf dosi n~ than 10 tilt" actual dosl' uv-d or coucentratious produced. Tl lis lx-havi or fur lIlt'tllol n' x.alt· can ht' t·.\ plaillt't! hy its act ivity as an anlimdaholitt·, It tuhrbns dtbydrofolatc reduct ase. Ihl'n'by prt'\"t'nli ll ~ lllauy 1I\I'tl lylai ioll react ions in the Ixxly. These reactfuns can Ix' IuhjbIted for sho rt periods of lillie. a ft'\\ ' tb~'S . \\i lho lll (~al l.s i n~ lrn...'t'rs ihll· tlalllil~{, . \\1lt'1i 111l' l'SpOSllrt· is suffidl'T1lly prolonged. IlIJWt...vr, tilt' tll ma~t· is im...·t·rs;hlt· and po lt'utiillly Id ha l.
TIme Delays ,I nu-asun-d re s!'N )I1St· to flllly rt'i lt'('f :1 ~ \'(' Il pla-SIll,1['(1I\('t'II" then. tln- ('ull linllomly dlall¢ ng I"t'spnnse makes allY cnrrelutinu betwe e-n n'S!'MJIlSt' anti plusmn conccnrranon t·.drt'llIcly d iffit11lt 10 establis h. Ont· source o f tln- t1l'1ay is till' tinu- n-quired for t'ljlli lihnllioll 10 Ot"l111' hl'''wt'li
It o fte n takt·s sonu- tiuu- fnr
trutton o f
dm ~ . Unl il
al lilt' sitt' of act ion , usually ill a IiSSIIl' , Thi s tlday may ht· sho rt if III(' dm~ t'nh'rs III(' tisslle r:lpid ly; Wht'lll'lTtdin', lidocanu- supprl'ssl's ventricular an-h)1hmi a.s wit hin a few minutes of ¢\i n~ ;j IMII IIS <10M' ; thiopt'nlaI iudu('t·s am'stl lt'sia ewu mon'ljukkly, wh en till' ta rgl'l organ r('sidt·s in a slow ly l'{lllilihf:lt in~ tissue, the dt'la~' Illay h(· Illan y hou rs. f or esampk-, tilt' mudmum ca rdl,u- d Tt"l'fs o f t li~ox i n are 110t seen for ,III hou r o r more after adlllinish'rill ~ all Lv. bolus of lilt' d mg. Anolllt'r soun-e of t1t'la~' I~1II urise when Ihe n 'spelllst' monito red is all imlin."l'f lIlt'aSlln ' of d m ~ t' rTt'l'I, A (h lll~t, in hllMM I pn'Ssun' is an im lin"l'f Illt·;l.s ure- of t' ilhN a dm n~,' in lJt'rip llt'ml n-sistance-. in mnliae outpul . or ill both. Plasma uri c acid is anulht' r (·umplt·: ln-n-, tilt' di rect t·fTt"l'f is all altN'dtion in uric :wid wnt hesis or elimination. Yl't another r-xamph- of all uuhn-ct n.·SPOIlSt· is tln- dlan~t' ill tilt' 'St.'m lll protlmnulun t'(lllIp lt·x al'fh;ly produced hy coumarin oral a lll ;(,(li.I~l l.lnl s . Tilt' mon- di rect t·fTt"l'!: of Ihl'S<' :lnlit'( );.l,glllani s is 10 inl lihil s~ll t l lt's is of tlu- prothmmhin compk-x. Tlu- dt ·lay ht'lwt't·u aUainmt'lll of" pLl..ma l'(IIlI't'lllnllion am llll'l\illlill im!;n "l'1 ...rTI't.'f \·aril·s. Full rt'sponS(' in hlolKI pn.·sslln· to a ehall~t· ill lX'ripl wr:t1 n 'si stan('t' or in e .lrt liae oulpnt IK'l'\lN \\i thin millllh 's, wllt'rt·a.'i lIl:txinml rt·.'ipeJIIS(· of thl' pmtllnllllbill l'tllllpll'x al'li\;ly 10 \\~lrfari n ;s lIul S('t'll for J 10 2 t1a~'S aftN an o ml dOM' of Ihis an lil,(li1h"lllant ( Fig. S- 7). Uril' ad d ;uld tilt' pmlllrtJlllhin ('()mplt ·" art' t' :Gullpll"s uf t'lldtJ!.:t·1I0llS m;ltt'ri"ls. Su ch mat t'rials an ' t'tllliinnollsly ht'ing n ·1lt'\\l'(I. \\i th Iht· peM)1sin ' n'fl l"l'f in~ tilt' bal an t't' ht'''\l''('11 input ami loss. TI ll' impad of dlallgl'S in inpul and lus..s Oil tht' kind it's of t' "do~~1'1l0IlS (,(lInpo unds and lilt' appruprialt· inlt' '1)rt'lillioll of sueh da ta .m' (,{)\l'f('tl ill ~n'at t'r tll'I ail in Chap. 2.1 , Tumnw r COll('t' pts,
MODALITY OF ADMINISTRATION AND THERAPWTIC OUTCOME As Illt'nlifJl lt'd at th l' I K ·h'; n n i ll~ of Illis dmpt l'f. lIlainh·n'lIIl't· o f a plot'iUla ('olll't' nt rat ion is not alwa~'S a dt·sir:thll•IIll'rapt'uli t.. olljt"l'fi\'(', So mdill1('s, a ll ll d llali n~ {',(ll1t't' lltr:tticlll is mort.· t1t·Sir:lhlt·. \I ud . t1q X'lld s 1m Ihl' plm nJlal'(KI)1l;U11i<.' fl'ahm's of t·ffiedt'y amllo:-.;idly. 111is
..
THEiAPE UOC RESPONSE AND TOXIC ITY
CHAP1£R5
~
0
~
12
1l
10
~
nfl:. S-7. 11... _J II~J, n "'I"""" in ""' 1'1;. .11... 1,"111,,,.. nl " ,, n "" I'Io·\ ii< il)' I" inl,ilo,ti"" il>
"r
~lll l ...' i' I,>' ...... rfarin
B
A''I1 ' I),.· i". lin 'l1 "..I" n · ur,1.., "",;"_"ft·''' ''''1 ,<1 ,t..,
6
.Io ·ft·.."
~
0_
~~
~-
;:
4
~
E
e ~
E~
.10
2
2
0
3
4
5
100
..,"" ou ~ .s ~ ~
~ E "0
u~ ~ "
c_
c1l~e " ~
~E
~ 0"
z
75 50
•
lO r ".-arf,ui" . ,I..• "''''1'1..\ ..l1i\il~·
tI,,· 1i"'1 ,Lty. II", ", rf;onn i_ . " ffi<.i<..,1 I" ;01".." 1 •.,,,,. lio..., "r I"'... ·~ h" .·~ •• ""pl \~ " I I " .. i• . " . ..... arf..ri" ....... ....tr.dir..' r..II•. II ~1' 1 1 ...... r..I<' "r II...· """1'1.·, ir K"" ';"" " ..,..II,,· .f'll,r ' ''I" al. ,I r..I.· "f "' lal..... "f II..• " ""pl.... 11,,·n·af!<" r tI, II ..• \\1l11,,'!J I
.1."..
.·rr
25 0
2
0
3
4
'1"lM li ~
U" ri,,~
n..·
5
Days
polnt ts well illustratr-d wit llllw alltimkmbial a,gl' nts, '1111' p urpO!i(' u f ;Ullill1 k m hial !Iwrap)' is 1111' I'r.lt lie ,llillll u f an infl'(1 iu ll with minim a l tm;id f)', Figt lrl" ~ s!tows m aj or difTI' n 'll('t"s in Ill!' t,(f1"l1 of t1ns in ,g fn'l IIlI' 1l1')" u n lIlt' ( ltit~· dOl"!'
1000
i,rud .. ffic.'''''Y in ,,,';
(I<..' lu Kk-l..j,,-I14 I" ....","lnw ill
'It"",
' n 'P'·" i.: mil..· _.. riM " ill. Ill(' ",,,Ii · m iMt,hi al ~'t'1'I . \ \l,,·n >a.< ".. d1a IlI(.·
111
.l.oi l~·
,......" ..1 .. i llo
100
~'n l ...
,nI<1" (1.Lot ''I'''''). ,m...h Lt'W" r
r""I,,,..,d~·.
1" 10.'<1 1,
J.E..
t·..nli". a . t:I"·,,. s .c., T.II'uL.. K.,
10
\ '. ""4n",,•. It " ... ,,1 CroliR, W.t'., O " " I",r..tt
rr...
;Illtihiot k ." ....•.... 1 f lot'wral (I.n".i"~ i"lt·r. in ",,,rin. · i' ",..",,,,,,ili' al..1
!'t·!:tl io.ltll-I!ip
,.,.j,
Ihij(l•.inr....1ion ,,1011.·1•. J. l" r'''-1, 1m .. 1....'1,2'l I-29'2. 1 9"~ , )
o
2
4 6 B 10 DosingInterval (Hours)
12
( HAFTH 5
.,
Ccftazidinn-, iii\(' other ~- lal'till n unt ibiorics . exhilnts onlv Illininml concenrmnon-deIx'm lt'nl bactericidal l!l.'l hily. so Ihat bactcrtal ktlhug is more d,'pt'lllll'nl on time aho\'(' the min imal hal"h 'ridlbl roncent rution than 0 11 the lII a~n i tude o f till' d n , ~ coucent ranou. (;n 'atl'T Ix'nd it is tln-refon- adlit'n '(l with ilion' frequent ad minislra tion Ihat minimizes tht, possibility of tlu- plasma concentrattou falling too low, All add itional reason for frequent ad ministrat ion is thai 11ll' d uratio n of thr- pos ta ntihio til' d Tl't1- wh eI"('!Jy bacterial I-.trtJ\\1h is supp n-ssed fo r s( 1Il lt' tune after Inte r mitte nt ('XIX1Surl' of b acten a to th e unn nuc r obml agl' nl- is \('1) ' sho rt with rln- ~ · lal1 alll antibioti cs . In cont ras t 10 l'l·ft,tzid illl(', ~t 'III;\l llid li alld ntl l('r alll i llu~IYl·o..idt'S pmd lll'l' a pmlml ~t'(l postan tihiolie d Tt'l,t, T ll('y also exhibit marked couce ntranou-de-pe-ndent ki llill ~ O\"l'Ta \\idt, TiUl}!;l' of cour-eutra tious \\i lll h i ~llt'r \~lh ll'S ha\i n ~ a mon ' pnmlJlllll...'(ll'fTt't.1 U II ti lt' raIt' am i extent o f hal1t'rid tlal al1h i ty , :\l'l·o n.lingly.largt' lnfn-quent doSt'S of gen tauucm an ' ,lS t·fTt't.1in' and po te ntially mrm- so than smalh-r mo re frequent O Ill· S. A ltholl ~h data in pal it'lIls with infection s, of IIt'l't'Ssity . an' mnn- \11riahlt, th an those ohta im'l l ill lilt' experinu-utal mouse modd. tht,), do tend to Ix'ar out tbe findings ill Fig, ,5-Ji. Mon-ovr-r. stud ies ind il"dtl' that rlu- lIl'ph m loxicily o f tlit, alll i n~IYl'lls; dl's can 1)(· redlll'l'l) hy a onl'(·-daily n-w nll' n comp an -d to more fTl'llut'nt admi nistration. n lis ma~' explai n tilt' It'm lt'lIl' ', ill ~l lll t· IIUitrtt'r.i. to 1l\ 1)\"l' From a Ihri ' ...·-tLtily 10 a olll'(·...laily ad mlnts trat ton of ~t ·ll t alll ili ll .
ACHIEVING TNERAPEUTIC GOALS Chapn-rs fi am i 'j pn'St'lI1 till' basic principles fo r l'stablishi n~ and t'\"dlna!inJ!; dosa~(' n~ mens for th ost' d m gs thot! shu\\' n"I.-"'JIlahly valid com-Iatlous o f respo ns(, \\i lh dose an d couceru ranon. C hapte r 6 t·xamint·s featu res of constant- rat e input , while C hap. 'j e xamines tilt' prtncipk-s 1l 1l(1t' r1~i l1 ~ tilt, administration o f d rug ill disc rete du st' Sto attain andmaintain tlw mpt'llt il' l'lllll'('niralions. SO Il l(' mltlitional l'lllllplt·xi!it.s of till' concentmnon- res ponse rt'lalio nship an' addn-ssed in C hap. 20. P!laml al,(ll( ~(' He-spouse
STUDY PROBlEMS lAnswers 10 Study Pro ble ms o re in Append ix II .)
I. Dt'fim ' till' It'TIIlS:
2. 3. 4.
.'i
a . AII -or-nom ' n 'spollSt', b. ( ; radt 'll n ·sl)(JIISt'. c. Tln-rap -ntic \\illth,W. d . Utilitv l'IIT\"(" e. Toh-runce. Explain why t'1li.'l1 (de-sin-d lIT loxic ) is ofh-n 1M.'ltN co rn-luted with p laon« con centrntin n than wit h dust" U s! uud brit·lIy t1iSl1ISS four sit uati ons in whic h poo r plasm a d m g couceutrauon - rcsl)(lns(' n-latlonship s an ' likl'1y to occu r. U s! the plasma concentration r.1Il~(·s l,(lllllll(JIlly a.'isociah 'll \\i lh tht'm lx'll tic n"SIXlllSl'S uf cyclosporiru-. d i ~oxin " ~t 'lI l a mici n " lithium . plll'll Uharhital, pln-nctoin, and theoph, lIint·. 'Bril'lly discuss, with examples. 1\\11 situations for whidl f rt'l IIll'Il(." o f udmtutstratlou o f lilt' sa l1lt' daily tinS(' alTt'l1s tilt' therapeutic out come.
CONSTANT·RATE REGIMENS
OBJECTIVES The reode will be able 10: I. Define pIoleou and describe the factors conrrolling it. 2. Descube the relationship between hall~,fe of a drug and rime required 10 approach !he pIoleau follow-ing a COI'lslOnHOIe inpur wim or Without a bolus dose, 3. hlimole the values of halHile. volume 01 dislribJ!ion, and clearance ofa drug from plcnmo concentration dec obtained during end 1oI1ow-il'l9 ccoscoecie inpur. 4. Eslimole the values 01 holf·Me. elimination role COO$lOnl. and fJoetoon excrered unchanged "om urine dolo obloined dlJl"ing and lolbwing COflslOnl-role input. 5. bllmole the valveof [enol clearance from combinedplasmaand urine dolo 6, Use phofl'l'lOCokineti<: poromelels10 pedct the pIoYTlO drug concentration and the amount of drug in rile body wim lime during and following coosontroe input wilh or without a bolus ccee. .\ S i ll~II' do....· may rapidly procllll't· ;t t1" ,i n'~IIIll'rapt 'llt i l' «mcentrauon . hut this mode· of administration is Il1lsuilahl. · wlu-n lIIaillh'IIisi'l ll is dl·, in ·t!. :'1:0 ether mod(· (If administrutioll pro\'itlt·s slldl prt '('iw ami w ac!i l.\· ( ~ lll t rolll ·d dm ~ atlllli llislralio u. It is. how('\'t'T, n-stricted p rima rily to IU I' pital M ·lt ill ~' . .\ \\id"r applieal ioll of (~ JlIs l a llt - T'2 mill. '>0 IIU' dTH l..( is in fu"l"t l fOT al)(1II1 IS half· lin ·s.
DRUG LEVEl-TIME RElATIONSHIP S ., tim !!: is said 10 I.... · h
..
67
CHAPI[ i! 6
infus ion o f a ho llis dost·, t ilt' duration o f ouotant infus illt l is IISIIa llv IIlI KIIIOII~t'r than tilt' half-lift· of tlu- t1 m g:. T ilt' t·<,st·ul iu1 featun-s of rln- t'Wllts followin~· a constaut lnfusn m (':111 1M.' ap p rt"t: i:lh'il hy l'un sidl ' ri ll~ tln- ('W ills
The Pioleou Value :\ t an y t imt· dll ri n~ an in fu sion. tilt" run- of d"lIl~t" in tlu- amount (If dru g in till' hot ly (tI.Vtltl is tht" t1i1Tt"n·m'i·IM.·h\"t't '!1 tilt" rates of t l m~ tnfuston am ] elnulnanon.
dA
"' or
t·\prt·....ill ~
tilt' equ.uton
k· A Cc euc nt role o f inhJsiOll
Rote 01 el iminotioo
ill terms uf the concent r atton
of d m ~ ill plasma.
Used lor i v. infll5ion Soma ~ a le pcrtIble. o/he<s O' llt implanloblllt
30.60. a QO mg/dov
001
odm,n'!>Iefed do,ty
f't>enyIproponolom'ne
25 rng rrreedoe ,eIeo~ and 3 4 rng/ht for 16 hr
Coburn ehannelblocker l\Iond's,nltlg'Ol,ng S)'S1em is designed 10 proede a eonSlont 'Ole 01 -eecse lor 2411, Appel'1e suppressont System o,ms 10 prov;de a (OI'\$lQn ta nd effecb...e plasma ccecewcrce 01 pher¥prop:trOOm'ne
16_ Tmn$do><mol
00501 0 .1 rng/ doy
for
Treo lmen t 01 menopausal syrnplOm$ and pl'l!'\I'llI'lt>Oll
01 O5IeOpOI"O$IS
AppIoedlO Inlrd:, 01 body. inck.d"''oQ bullOck! a nd abdomen. TWice ~ty
7, 14. and 2 1 rng/doy (40 ltg/ em1/ hrl ehonged doi/v
o I 100 6 mg/hf oYttr 1211,
b"0'''''''''''''' .
M Pr~ a 'eoloOllObty conSlOnt plosma concenllQ1lQtl 01 nicotine Polch pIoced on front 01 bod above 'NOIS! 01 on uppe< outef pert 01 o'm p.ophy4o.'s ogoinS! ollOCk 01 ong,na pectoris Syslem a"T~ 10pl'ovide a (OI'\$lQnl plasma concenfTCll>Oll 01 nillC9!ycerin Recommended oppliCOl>Oll S11e
o 5 rng CNef 3 days
's Ioleral cbes M;lW
U~
lor prevention 01 mellOn
"'.......ho,f\es.s Applied 10
area
behindeo' o, leos/4 hr beiee theonl~1( elfect
n deseed
.
CHAPTH 6
CONSIANT -iATE i EGlrW: NS
t'IJt. 6-1.
1>Ln",,,
n l l'
lUll"
't
•
1500
lil.., "r11,<"""I'hulll ti . ....··t)l I'I".... l1 ,i''' 'ltl'1l * :1;,.,,101' (I· PAl rapi,Uy .. 1'"_·1 hmiti nl': ,....,... in .. patit >!lI ....h n n-c i...'. (UU Mt·j!,.. " n il "/ rnin
/ 1.-1 ruWlIlin ) ~' ('t'fl>tallt'TlIll ' in f,, "'''' rur /:Ill ,n ino At th. ' " utl u( II... infnsiun. IIo" I'I;o." n.. t· r A ('t" K't'nl · linn tin, .. r"l"'lI)' 1, ........1 1' ....' wilh .. S.2-min half·llf... nN ' li".. i. til.. f"ndi" " C . 1320 ' (1 _ .. _ Q lnt) l l" ri"~ tI.., i " (,,.itll ' .."tI C • 132l1 ' .. - 0 .1. "',. ..
lI...n''' (''-' ' TIlt- , ,.Ju., ,I
1000
500
11,1.11. mill - I ('Orn "l"",t!, In ;a h"tf· lift, uf 5.2 mill . (At4Jt 1 ("»11 K...•
t',.c......". .
10'1'. KW.•
Ka'f'l·r.
\ lIn
A
KI" rl. C .•
til., Williw, I'.A.•
o
"".1 W....tl...rJ,.·, R,C.: n... rJ...n nll ' l'o ~ i '1l'lk. of dcubl.. -charn ' · I' A (d ",,~):
en,,«
or I,,>lu> injo"C:-
o
40
80
120
160
Minutes
lin" , in{" ..o.... a,.. I . I",I"I" ...41i"" I.,.· ....-i¢ ,t in p;dM'1,b "'itt. rn~' Il"olnlial infa,,";" ". elin. l"hann;K", 1 n ......
5O:2fi7- 2"jj. l!:l!:l l. )
100
t
90
-, From infusion
75 ~ ~ ~
~
<;
50
C
~
" ~
a.
25 / From bolus dose 0 0
.' 1/:.
_t.
2
3.3 4 Half-lives
6
6-2. Th· "I'I,.. In p1ah...u II n,,,tn>l k..1"n ~' I", t1,,· lt.df·lif,· o f II,,· , In' l: D'1"'-1,..1il a ,illlal;'", in ",,~, id, a 1".Il1s .k...•(ll imm,..b.I"I:o· a1 lai"' ...1t! a n ""lanl i" f". Ior, tl..• af" ·T """inlai". ;o ,..""ta"l ," ,,,",,,1iu Ih.· "' ''~' . A. th,' "",,"ml of l.... l" oIns ' k...· ft·mainillll: in II... I " >t~· falJ.. I ·.... i' ... ,"'rnplo·I1 "l ary ri,,' " ..,,!tUlle: 1'1'' '''' tI... inf" Iit>!,. 8~' 3.3 It.df·li,'t"5. II..• a,,,,,,,,,1 In 11... I u.~ ...." ,,·;;." ..1 will. II..• i" f"';'111I n·;o<·I....1 YO'.'- of tl,,' I'LtIt·;ou _,J,It'.
CHAPT£ ~
CONSTANI-RAT£ ~£GWolNS
6
dC V · 71
= Ro - CL · C
.. 2
On s l a rt i n~ a constant in fusion. ti lt, amou nt in rln- bodv is zero, nndlu-ncc then- is no el imilllitillll; thi-n..fort" amount ill tilt' hotly rises . TIlt' rise con nnues unt il ti ll' rate- o f d imlnat ion lllatdws tilt' rate of infllsion, Amount in th e hlxly am l plasma ccnceutratfon lin' tl u-u said 10 ha\'(' n-achcd a '\'II'm l 'J sta te or "lalt'(I/1, wh k·h continues as I() n ~ us till' same infusi o1l m h o is muintuiue-d. Silll't' till" rate of d lilll~t' of amount in the IMKly at plate-au is zero. it follows tllat El ls. I am i 2 s i lTl pli ~\' to :
Roll
=
A. AfTIOIJnt at
Infusion rate
steady stale
Elimination role constanl
c. Concentration at steady stote
•
RoICL
3
4
Infusion role
Clearance
Cll 'arly, lilt, only fadon ~o\'(' m i n !-! amount at plat eau an' tht ' rate of in fllSion and lilt' eliuuuatiou mit - con stant. Similarly, on ly infusion ra ft' and dl'aroUll"t' cou tml the stt'ad ystall' ph~ l1la t"tll\('('ntmtiOll. SUppU<;I', for illllslmti\'t' purpost's, that a slt'atly-sla ll" phl-~ Tl1 a Iheuphyllille l'tJ!lt't'nl ralioll of (,5 mg/l . is dcst n-d in till' pa lit'nt whoS(' i.v. hoius da la ansho w n ill Fi~, 3- 1. Sim'{' tilt· dt'arolll{'t' uf this d m ~ is" lAir (C hap . 3 ), tilt' n'lluirt"tl in fusion r.11t' is 60 lllW'lr. As ti lt' t'limillation ratl' constant of Iht'C lpllyllilll" is 0 .14 hr - 1, till" {'(IITt·SIXllltlill,g amount o f tlm,gin till" IMItI)' at stt'ady stall' is 4V) III~. Altt'nmti\"d y, Ihl' amount cun lit' (".lk·lIlah 'll hy lIl11[ lipl~; T1!!: tilt' plateau {'oll('t'n tm !ion ( 1.5 mWL ) by tilt' \"UIUllW of d ist rihulion of tllt'llpllyllilit' ( ~) L). To l·lIIp lal~~i:t.l.' tilt' fadon; tllat con trol the plateau. conskler til(' follU\\ illg statement: All d m~s infllst'tl at tilt" . ..u ue r an- und hil\;ng Ihe sallie dl'amlll't' n-ach Iht, sarne platenu com- entrution . This st,IIt'll1t' nt is tnu-. 111t' liver and kid neys ran d ear n l\I~' what is p rosenn-d 10 tllt'lII: tlu-v art' in<;l'milin' to di (ft·rt'Il{'t's in tisslll' distribution. TIlt· rate o f ehmimuion t1q"M' lltl~ onl;' Ull dt'aml1t'{' and plas mu concentration. At plateau , mit' of di minatioll is l'l lual to rate- of infusiull. Th e pl :~~ lIl a l'u nt'{'lllmlioll must then-fen- 1M' tl lt" sann- for all dm,gs \\i tb tilt' "m!?:s wtth the Sillllt· half-lift· han ' lilt' sunu- elimi nation rate c uwt.uu . TIlt' di minatin n rate constant is tilt' [ructional mtt' u f
7.
CONSTANT RATf REGW,fNS
CHAPTHO
p mdlll't· a plateaueoncent rutkru of 10 lllWl.. sinre an infusiull rah' (If fin m~~/" r results ill it
plateau couceutration of 15 1II !ifl ~
Mean ReslderK. Tune Conceptually, a useful pardn wl N to (]t·scril lt., tho sojourn of t1 m~ in ti ll' (Mltl>' is mra n n·.~idl'lln· t jllu' ( .\1 HT) , T o appn'<.i atl· its rt'1aliollSh ip In (1111t'r pllanJlal"okim ·t i{~ rxlnUllt'lt· rs . consider tilt" Iufusam situation. Fur it ~\"t'1l constant run- of infusion. till' amount uf d m~ ill til(' hod)' at slt·ady ..tate- [ rat e- o f r-liuunathm "" roth ' f)f infusio n ) depends (Ill rlu- time all a\"l' rd~t' 11101('(.' 11](' n-stdes ill tilt' Ix)(I)'. For ex a m ple. if 2 X 1U1I1 lllo ]et:u l("S are d i mill ah 't!
pe r hour ami ti ll" reside i ll the hlxl)' for 10 In , rlu-u only U1w-fl'nlh of tILL' molecules in the hody a n' n -movcd IX'" hour. l111'n' must tlu-n-fcre lx- 20 x )(~ ' mul'~'II,·s i ll tilt' "ud~" TIllis. .\fRY is related to , II.. infusion nil .. and th.. a IlMHIII! in tilt' h,lt l} I,}' l i lt, ""!.IIiUIISllip :
MRT =
~
MRT ..
I
6
x ' 1/2
7
5
F rom Eq. 3, it is l'\ id t'lit th a t
1
o r, as k "" 0.69.11'112
MRT
~ I .AA
Furthen non-, a.. k "" CI./\'. it follny..s fmm l-~ I _ 6 tllat
MRT . VI et
8
For t11l"'C )ph yllilll' (\' "" Z9 1.. CI. "" .. L'hr iu t he' patient ('_x.
rune to Ream Plateau A dday alwlI)'S e xists 1)(,t\\'t'(' 11 the sta rt of an infuskru an d till' t'stablisllllll'llt u f p lateau. The sol(! Iacto r l"l llli mll i ll~ the approach to plateau is lht' hal f·l if(' of tilt' t l m~. To appn-ciate this point. consider a sit uatio n in whid l a IMllus dosl' is ~\"(' n a t till' sta rt of a con stant lufunon to illlJll('lliatt'ly a ttain th e amount adli('\ '('l l al plateau: clearly. tlu- si11' o f lIlt' hu lus d ust" m ust 1)(' Au . Thereafter. the- a mou nt ill till' hody is maintained at IIIl' plate-au \1llm' II)' constant infusion , ImaWlll' thut a w ay exists 10 moni tor separately dnl~ f(' llIai n in~ in lilt' htM)" fm m tilt· bolus a nd th at al'l'1l l1l ll lat i ll ~ dill' to tln- Infu sjon. TIl(' events are d l'pid t't l ill Fif{. 6- 1, I> m~ in tlu- hody ll"~l(..lated with eac h II11 Mlt, of ndmim strut ion is l'Iim illa!l't 1 ll~ tl l(Jll~h till' other were not p n-sent . TI.t' amount ll"S(M :iatt't l with til(' hulllS doS(' declmes l"xpollt'nlially ami al any time, Amount remoini...... in tne '" l;I
body from bolus dose
However. as
lon~ as
•
A
..
•
e _..
tln- in fus ion is maintained. thi s rk-cluu- is
9
eXill11y lIlaldll'tl by
71
til(" ~ai l1 n '~lI lti n~ fm Hl lilt" infus ion. This mus t ' " " SCI siucc till' slim a l\\ll}'S t'(l"ills lilt'
plateau. :lou ' It the refo re follm\'S that the amount in tile boJy a.~~.odall"d with iI constan t infusion ("""nil is ill\\l l}'S tln- d ifTt'rt'lll "l' hd'w{'('11 tht· a mou nt a t pla teau (A ,.) lI lId tilt' ;UllOIIIlI rt' lIlai l1i ll~ Frmn the holus dust", namely.
amount at
A ,,,1 _ A .. - A ..
' \9 - "
10
O r. hy d i\i tl i ll~ t hmll~" hy till' vnhmu- of d islrihlllioll.
....
...; C"" - C.Jl - . -',
11
Thus. hulll lilt' umouut in tilt' hotly illld IIII' plasma couce nt ranon (e ho/) rise a.")·lIlpt oli{~dl1y to ward rt'spt"t1in ' p latea u values follc)\\ill)tconstant- rate d m~ infusio ll \\ilho ut a holm. dUM', TIll' ;111I0 11111 of t1m,g in t 11(' l)lMIy. Of plas ma couceutrutjou , t"X pn.·ss.t't1as a ))(·rt",'1I1 of till' plait-,llI vahu- at difh-n-ut limps after initiation of an infusion. is shuwn in Tabh- 6-2. In I half-lift·, tilt" vuhn- in 11ll" htM.ly is .')0 '1 of tho plateau value. In 2 half-Ih '{ 's, it is . 5% o f tlnplah';l11 value. Tln-oretically. a plate au is only n-acln-dwh en tIll' d nl ~ has 1M."l.·Jl infllSl"l.1 for a ll infinite III11nlM.·r of hal f-lin 'S. Fo r pracncal PlI'l)( ISl'S, howt'\'{ ' r, tht· plan-au lIlay he consitle ft'1l lu I M.~ rt·adlt"l.l in 3.3 ha lf-lin 's (90% of tilt' platea u ). 1111lS. the sho rter tilt' !lalf-life. tilt' SCKll\(' r is tlu- platcuu n-achcd. Fo r example, I- I'A (haIf-lift· o f .S mill) n-aches II p b te au within minute-s (3 .3 I.alf. lin ·s is 17 min ), wlwrt'il.s il tukes 2 to 3 \\'{'(· ks of cousta ut phenobarlutal admlrustration (ha lf-lift, of 100 Iir) 1M.'fo rt, tilt' plateau is n-ached (3 .3 hlllf-Ii\'t'S is 1-1 da ys ). 111l' important point to rememlx-r is that tilt' approach 10 pla teau depends .~ Hf'i!J o n tilt' Imlf-Iift, n f tilt, dOl~. Fur t''(a mplt',!''''(-,lIlst'' the half-lift' o f t ht'1lphyllillt, in tilt' esamphpatit' nt is 5 hr. il must I"" Infuv-d fo r 17 hr before plateau is n-acbedTlus is so whetln-r flO mwllr is infust'1l to ma intai n a plateau conceutratiou of 15 mWJ. or t he infus ion run- is hak t"l.! (30 mW'llr) to maintai n a plateau concent ralion of 7.5 mWl... In 1111' fo nllN case, tilt' t h''11phyllilJ(' pllLslIla coucentrutfon at om- half-Iifl' is one-half th e co rresponding pl ate au "ai m' of 1.'5 lllWI•. So. if O lll' want ed In lu:hit"\'t.' a p latea u concentration o f 7.5 IIlWL ill 2.5 hr. 0I 1t' woul d infuSl' a t a rate o f 611mwl lr fnr I half-life a nd then maintain this couceutration hy I mhl l1 ~ tilt' lnfusum mho In 30 mWllr.
Postiafusion Afh ' r S I(Jppi ll~ an infusion . tilt" amount fa lls hy one-half l"d(:h hal f-lift' . I lltlt't.'11. wn'n unly till'
,
c..
0-2. P.rc••• ef the ""..... Le....._he4 .. V-'_.
I.....I_ .. ~
tI_. .....'"
"'"
PfKIMQf
05
'" "
1... 1.,Il...,j
I
2 3 33
, 5 6
7
50
75
90
Q' Q7 Q' QQ
f.U.wI. . .
CONSTANT -RAT'E
72
CHAPTH o
iE ~ NS
O f 43 Ill~. n-mutus in ti lt' hody. 111t' SOUl II ' amu unt of would he found in tlu- hndy Ii hr aftt-r an i.v. bolus dost, of .t2S III!{ of tht·ophyllilll" Aftt' r rt:'1!l("inf; SO IllI' transdermul constant-rate rd t'iL'>(' dt... k t·s, dn l!-: {'o llti lilles to hi' n ·lt'il,>(,(! (m ill h indillV; silt-s in sk ill fo r a p p reciabl e pe nolls o f tune. I n ,!JeSt' in sl' IlWt's. t he plasm a dnl~ {'olll't' nimthm falls mo re slowly than afte r sluppinv; an i.v. Infus ion.
only llIw-tenth of the plateau vuhn-, d n ,~
Chonging Infvsion Rates The rate of infu sion of a d ntv: is somet imes d ,anV;t'tl du rin!-: 11lt'r.lpy ht '('llll'W of e Xl'( 'S Sh l' lo'(kit)' (IT au illal!t'(luatt' therapeutic n 'spOIlSl', If ti ll' object of lin- dlilll!-:( ' is to d Ted . a uew plat ea u. then Ihe tinlt' to ~l Irom ollt ' plnt euu to anoth e r, whel llt'f hiV;I11'TIl l' JOW I·f. dt'lwm l~ .yo/e/y un till' half·lift· of the dm,g. Conside r. for Illustrative purpO!;('s, a path-n t slahili:f.t'i.1 U II ;l 3H' IlIWh r infusiull run - of t1woph yllilll'. which al'lunl ing In Fig. fi-3 should prod ul'(' a plateau conccnrr anon uf 7.5 m wl~ Suppose rlu- silu at io n now demands a plateau t"llllt"l' n trati u ll of 15 mw'l•. l 1tis 11(,,\\ ' plat eau value is achieved by doublin~ tht, lufuskm m ho tn fin mW'!tT. I lll a~rj l\t· thai inslt'ad
c
15
0
~ :c:l
" 0
10
u
~~
................. " ..," . -
>' E
~ ~ 0 ~ ~
5
~
~
E ~
~
0:
0 0
4
8
12
16
20
24
Halt-lives
li""
. ' IK. fi.-3. Sil""U.." III".lr.. Ih.ol tI,,· ti".. , I.. ....;00:10 " ,.._ pL'I"" " . ",1H11...r I>i~lt' r " r lr"",r It,,,,, 11"' 1'''''irHI' .-..],It· . • ''' 'I)' . ", tI... l....f.l;f.. uf" dm lit· A pl"I""" t"'I(~·" l rati..n .. f' oS m:o:t1 , i , "";00,1"..1 i " " pp m\imall'I) 3.3 tl"'f· lln~ .oft,' r ' I"rti"jt .. t"",.t ;u,1 i"f",i
10.,....,.."
nW" hulIilllit :Jl1 mw1,r (tlo. ltlt..I I.w..·!tli'It·) ;llKl ' I"rtinlit ;ultlth" r t" ",lal,II " (,,,it,,, nf 3flllllit/l> r (m l"'l ..1,Lt.. I.."l lil" ·). In "l'p nl\i """" '1)' 3 ,3 h.oIf·li' " . tI..· 11""'I'I,yl1 il... t~ ..It~·" I""lit .., ri... ... f">llI' .S "'Wi. I" IS "':o:t1. 11..t.; " Iit " n inf" >it,,, ....1.. " f fiO m~ r i, lUll'!t'l(t 1m I" ,1' W nlit tI,.. 0" 1'I,1t·""·" 1....,.· 30 llI~r inf... it,,1. 11..· I'Lo.. " ", t"' K~'n lr"I i<", nf tI"~ 'rh~~lir ..· "P'l'n>••d ..-s ~ pI",•.•", " f 'i.s rnWl. in "1'I'" ,u m. "'I)· 3 ,3 h.:lf·Ii...\ ,
28
CONSTANli ATI ~(;O.'tiNS
73
of i ll(.'n·a."in~ til(' in fusion rate. tilt' atlditional ,'30 mw'hr .....as adnnrustered at a d iffl' n 'nt site and that a \my existt'11 of S('~lI'
Bolus and Infusion It takes app roximatdy 17 h r of coustaut infllSion of theophylline befon- till' p late-au concvntranou is reached. An ('\'('11 1 (J11 ~(,( lim e is req uired for dm~ wi th hal f· livt's greater than thai of theophylline. Situations sometimes dem and that the plateau he reachedmore mpi
600
•• • •
. '11(. 6-4, 11,,· r""'~'n.a ('O'l('(' nlr.ltiClllof ;O.:tin,lo , (I · PA) . I .. rl! ..I ..1""'1 .).'50 IUl m l. ( 1.2 J.IWm l.) ;0,,,1 ""I'" pn-11t"S p!at....u ,,( S'iO IU/m l. ( J. ~ I'W rnLl fotlt...i nl/: Iln 1.\'. 1" >1,,. of 10 "' II: a'KI a t'OIulanl-r•.r.. infll, ion of 1,6 mWmin fur 611 min Itl lUI irKIi\id ll..J ~1I1'jt,,<1 . Sui.. ' '''l ur nt l)', th r plum a ("<)nN' nln li " n dn'l" • • Ih.- dn. ~ inf" . it... i••10 1 III 0.3 mwmin , lim.. fn " n II finl ",•...J,. •Ialr 10 Ihr ..'<.'(_1 ,Io,,,·,ltl. " " II,,' half·lif.. of lho.· d nL~ 6,6 min in t1,is ." hjl 't"l. ( Lpt..d fmm K".tt·r. It \\'.. Collt'n f .. Klnft. C., Ka.
•• •
::; E
400 ~ c
2-
,. c
.e
" ~
u
c
n...
200
0
'-'
• •
o
o
90
•
PA (dUb,..........): t:IT 1s ..f 1" >1" 0 injt-c.--
180
Minutes
",.. p!uom"•.."tri'It'lx, of
270
lio n, in flloi"ns . and Imi ni.' ral inn 1,;.ill potllrnh wil h 1Il)-. ..... n lial In -
wri~'hl
fan:1io.... Clin, Phannao:-nI, n...r.5O:26j 27i. 11191.)
CHAPTER 6
CONSTANT-AATf REGWlNS
a, sot'i ah'(l with th e two 1Il1)(It·Su f ad mimstranon an- (:u mpltollw nta ry : til(" ~ai ll of (JIl(" olTst"ts t he loss of t he ntl lt"r. Sow t'unsid N IWO sit untbms. TIlt' first . SllH" 11in Fi g:. fh'5. is 0 11(' in whkll di fTNeut bolus dllS(°S a re' gin'n a t tlu- sla rt of a co nstant-rate in fus io n . In C,lo;(° A, tlmg is i ll fu~"li alom' a nd till' amount ri ~'s . rt',lt'h i n~ a plan-au of 2CX) m~ in appmxim:lh ']y -I hal f·liv('s. In C:lo;(' H. tilt· bolus tlOM' o f 2lX) m ~ tmnu-dtatcly all ains. aud ti ll" infusion mi l" tllt"ft'altt'r maintains the pla teilll amount . In Ca.'il" C . tilt' IMIllIs doS(' of .fUO IlIg is e xt't'ssh 't'; lx-causc till' rate of loss is initially Wt-°alt'r th an the' r ate of infus io n. amount in t1 uolMMly falls. T his fall {,(lIIlilllltOS until the sallie p latt'au ll' ill Case B is 1'('.\(:h('(1. It Sillmid ht· lIotit't"llthat till' tinit' to n-ach tht· plateau d t·Jlt·ntls sol ely o n t he half-lift· o f the d rug. '1111ls. in CaSt· C at I half-life . Jun 1Il ~. t'tlllllltlS('(1 of zoo 111 ~ n ·lI1.uning fRIIIl tilt' IMllus ami ]OU mg Imm tlu- infu sion. lit·s midwa y htOrn"("I'1I rhe bolus do w anti the pluteuu value. By 2 half-lives, ti lt' 2.5n lIlg ill lilt' IM)(ly lie s 7.'5% (If tilt' \'~IY toward lilt' plateau. By app nn:ima holy ·1 hal f-Iiw s, Iilllt· of ti lt' IMlllls dose remains a nd til(' plateau is reached . III C lSt' D. tilt· IMIllIs doS(' o f lUll 1I1 ~ is below tht' plateau amount . B ( '('U llSl' ti lt' mit' o f lnfnslou !l OW t'xt't'('(ls the rlllt· of dOlI-: e-limination, ti lt' amount in tlu- hotly {,(lIItinllollSly rises unti l till' S' U Il I' plateau us ill t!le
0;
400
oS ~ ~
0
'"
0;
Case A Infusion Alone
0
~
~ ~
300
0
300
'" .S 0
200
0
~
200
0
0
"0 C 100 0
"0 C 100
..
. 0
0
E
Case B 200-mg Bolus Plus Infusion
oS
.5 0
400
0
2
0
3
4
5
,, , ,
,,
»,
,
0
E
",
"
....
0
2
0
6
Half-lives 0;
400
0
2
0
"0 0
E
-e
0
--' -- --- -
",
0
~ ~
'" .S -,
,, ,,
,, ' .
"
0
2
"0 0
2
3
4
5
6
5
6
200
0
0 ' "
4
Case 0 l QO-rng Bolus Plus Infusion
300
c 100
0 0
400
oS
-,
200
c 100
0;
CoseC 400-rng Bolus Plus Infusion
oS ~ 300 '" .S
3
Halt-lives
E
. ...
5
-c
0 0
6
,,
,
, ,'.
'.
,,
, ,,
'"
... .
2
3
4
Hall-lives
Halt-lives
. l lt_ 6-5. Silll",lk..u il1l1s1rMI ,,~ I",", tI..· pLot...." .lol .·'Kb "pun tI... iur" , kll' r.... · ""KI "ol "p. M' tI,.. il1lli41 lo"tll' \\110:-11..-r iI I.~,~~ lo leh ..n (c a. B. e . D) u, nllt al II , I",rt or II... inf",klt" 11K' ",,,,,,,,"1 of c1",~ in tI... 1••1" "'I II..• r b " "UI il l h., mt· . ",.. ,"'.. .. "'1 uf tI... 11l ~ 1I' , n ·",..iniult in tlK' ,... 1)- ,.....];,,,.. t"Xf""wntial1~' (----) hill· tlK' lInKlI lIIl KilIl..d " illl i" fn,io:ll' in all , ri ,-,'mplutio::,,11) 1,,,,·,,,,1 plat...." ( . •d or ),;<> prnt "od I ~' c · .-\. I" e 11. e . a,.. 1 II..• .>1...·"',,1<~ K"~·lll r..I..'" (_ _ 1 I, tl..• ",'"
.w....
' ~ "'l'.
«:...t. .-\)
n.
Il1ili.o.ll)- acl,i< l it I..k "'ppn.l1i,m'h·I)' 3.3 half·li tu n ·.. pl"'I"a ll «(:as<" .\. C. I)). S ,It.· a.I", in ea...... A. e. "'Mil> tlMI at I h41f·lif,· allK,,, ,,1 in tI... lu l)-II... mid ay I ~ ..·" illihal ;.11I1 pL... .",,, ,,,,1,,,-, II.... "",,_\ \1Io:'n
' Kit
CHAPTH6
CQNSTA!'lH ATE
~EGWl NS
7S
pn -viouv ( ';N ' S is n-ached. O U( '{' again tilt' time to approach the plateau is controlh-d so lely bv th e hulf-Hfe of the drug. . Cav - IJ is dt'monstr;ltt'l) by t-I'A in Fig. 6----1 , TIll' holu s dust, o f 10 mg \I. -.LS insufficient 10 attain ti lt' stt'ady state achieved 0 11 infusing 1.6 IIlWmin. 111is result is expect ed fro m tilt' 6 .6 min half-life in this patit'u !. us lilt' " mount in till' hotly at plateau (ll./kl is 15 mg. In tIlt' sec ond am i mo rt' comm on situa tion. t1epit1('l) ill Fig. 6-6, the sa me ho lm dost, am ! infusion rate art' am! 'l-sso(·ialt'l l half-lift, vnhu-s . TIlt' half-lin'S ill the se- patient s arc 3, 6, and 9 hr. R-Spt"t.'tiH'ly, AIl);llic'uts start \\; th tht, same amou nt o f t1nlg: ill the bod>'. In putieut B. this amount is main tained be canw mtt' o f infusion is exactlv matched bv rat e of elimination . SilK" I'lim inat ion is slowr- r. ti lt' amount ill patient C rises until rate (;f ehmlnatton ('(Ilials infusion rat e. Th e finn- to reach this lugher plateau \'alm' is go\'e nl('(! St,ldy by the half-lift' of tilt' d rug in this patit·lIt. Thus. hy I half-life (9 h r). tilt' amullnt of d m g ill p atteut C is midway lx -twee-u tlu- bolus dost, anti th at at plateau . By the ti me the plateau is reached. all the ho lus doS(' has be en ellmtnated. Also . it follows fm m E(I. 3 th ai for a gi\l'lI infusion rate, amount at plateau is propo rtional to Ihe half-life . l1tis is see n in Fig. 6--6. wln-n- amount in p' toward tilt' plateau. and by 10 hr plat eau is
n-acln-d. 111t, apprcl:leh to platt-;1I 1 t1l1 rin~ an infusion has been p resented so far in terms of tlw time rt'llllin'(l (0 ~u from tht' initial cono -ntration (amount) to tilt' plateau. TIlt' lime to n 'adl any vahu - on uppr oach to plateau can ht, dd e n ninetl by t''OlIIbining the pri nctpk-s "I n.';ldy It'aOll,(1. Ht"t.·llllthat plasma cnucentrurion after an l.v. bolus clost., is C = C(O),- -l,. TIl(" roucent runon n's u l ti n~ from a constant-rate infusion is gi W Il in Eq. I I , As each t'\l'nl is imh-pe-nck-nt of tlw other. by Sll lll lll i ll ~ th eSt.' qeautmcs . one obtains co ncentration at any tim e du ring an lnfuston. Th at is. 12 For e-xample. if tilt' initial vahn- is 500 J.Igft., t!le plateau va hu - is 100 J.Ig/L. and th e ( ' UII ccnt ranon to 1.(' n-acln-d is 110 J.IWL, then tilt' ttm e to reach this concentration ca n 1)(· caleulah'( l a-s flllltJws, Ht'arran";ll g Eq, 12 and laking into account that ( 112)" = r - 1, (C hap. 3 . p. 23 ).
13 Suhs tituting for (; (0). C.. and C int n Efl' 13 yi elds (IIi
= 0 .1l25. Snl\; ng for n, a eouce-u-
tration of 110 I1WL is n -achrd in 5 ,3 half-lin 's.
Pradicallssves So far, tilf' appn l:leh to plateau has lx-en consfde n-d iu ahsolute terms. Pract ically. it is
lu-lpful to t'slahlish a tolc-runce, such ;L~ ± 10':1, for tln- final value. TIlt" HIllt" n:,(pliR't1 to hl.' within this toh-rance "arit'S with tile sta rti ll~ and final \lIlut'S. 111is may lit, seen I,>' application of Eq. 13. For e-sampk-. if onebegins at 80% of th t' final platl'all, th e Iillle to rt'at'h tht' !fJ\\l'r limit o f tolemnl'(' (90%) is on l>' I half-lift' , III (, mtrast , if the st arti n~ t"llll('l.'n tration is ,50nC! of tilt' final \..tlue . it takes 5 .3 half-lis'('s to n:'aeh tilt' lIppt'r limit of
7.
C0N51ANTv, rER[GlMENS
300
CI-W'tH 6
Patient A Halt-lite Shorter than Expected
200
100
---
·, ,,,.
,
o Patient B Half-life Equal to that Expected
~
'" 200 S
."2
,,
o
»:
--
·· ,, ., ° 100 ,,.. <5 , ',
, ,,
E
is
!i
. . ...
-I------.-:==~--~
0
Patient C Half·life
l onger than Expected
300
,, ,,, ,
200
,-
"
. ,,, -----
·' J ,r ,,'..
100
, ,,,
o
,,
o
'"
.... 48
24
72
Hours trMlIlK II.... IIw .moM,"! at ~ .. a" ... ".....t. ... ....Ir·lif.·. nit· ...,.,,,' I"J ut J._, , l 'n [""'liMllo A.. K. .... I C . ",Ih l....:Jr. In." of J. 6, Afld II I.", ""1'"1'.... 1y \ h.....p;t. ." nl "f t1NJt in II..• inotl
tl lC. 6-6. """.." .. ,,~ iU .. " ,\lMlI mf....... an- "" ,Ln 'l1 !',..,
,,,,, I .. Ih."if n"'l
Ii incb. " t half-lif .. f , ,.... "I ~"" i. m"' (polO
, HI, (1oI1..•.....,_
1J\~
(·1"'", !\ _
..ol oil.... 1. 01..0 do: 'UI>( (. • .) .. 'ilh hn il> .""lOInl in tbe- ho ..h '""' I ..'lh lhor n",",-,,! Inr ( Ia.oI.~ fNttt.rd ~ nt.. 01' inrll"'''' ~ d pa.t u in ' ..1:-· atlal 1 and onl i n lho- t... ~ (- - -1 (iw>~. w,tiI..ftrr -rP",.j ~' 3.3 t..Ir·In.."
.1
..........I IJ"'4'....'h .' AlMI C).
tI ..· Ii
..,...,od> on
I. Onlv
....d plal
ll k
CONSTANl-AATl:
CHAPTE ~O
~NS
71
toh-rance. I){~ of the final \01l1 lt·. Al'('('plin~ a tolerance clea rly modifi es the statement: TIlt' lime taken to rt'ad. plateau is ddt'nnillt'tl solely by the half-life of tlie dnlg, Now " ol li !II(' initial and final values must also bt, l'llllsidNt'tl. TIll' constan t-ra te n-leasc ~"li le mS marketed ma)' contain a Io.ltlin~ dOM' 10 facilitat e the mon- ntp id ad .it'\"l'lIIt·nt of th("ntpt'utit' l'llllt't'nt rat io lls, Ad minislt'rt't! extravecularly. however. with Iln- addilional absorption stt·p, the att ainm ent of both the-rapeutic concentrations and platea u wtll Ilu-refn re he 1001~t' r, alt hou~b perhaps mcouscquenttally, than that fellowi n~ all t'(llIi\'aleI11 L\' , regi lTit'll.
ASSESSMENT OF PHARMACOKINETIC PARAMETERS Pharmucokhu-tlc parau ll'tt'l's are gen erally ddt'nnined just as rt'mlil~' from constant-rate dat a as from L \ ', ho lm data. Ct'rtoullly, Ihis is so for an i.v. infusion . Foll{)\\in~ the IISC of constant -rai l' rt·lt,it\(, dt'"tees ad nums tc red extravascu lar lv, uncertalutv exists about hi oavailahilit)', whit,h the refon- requi res refe rence to t.v. data . S~lIt·tlll'll'ss, I;ow estimates of pilarlIlat'Ukillt'tit' jliir
Plasma Data Alone Co nside r, for rlu- 1Il01l1t'1l1. that measurements only dllrill ~ the infusion an.' amilahlt,. \\ 'hut can 1)(' t'stiumli 'tl? Finol. d hidill~ tilt' infusion rutc of 40 mw'hr by the plateau ro nc eutratiou of 9.5 mw'L ~ws ch-ara nce. in this (';.L<;(' .f ,2 LAIr. Indeed , thts is Ihe preferred met hod for t'St i mati n~ d earallt't-' Si lll't-· tht' plate-au concent ration can be de te rm ined with ~n.'at p reci sion byavt' r;\~n~ those l'tllll't·lIlr.ttiollS that dt·arly lit' al plateau. Second, the Italf·li ft, is t'it\ i1y ascert ained. being the ttrne taken to reach half tilt' plateau coucenrranou. !I()\\·t...v r. ill this example and ill most cases, no sempk- \\1l\ taken at tht s tinu-. and s.() mu- mus t interpolate lx-tween the observed da ta. TIlt' half-lift'. estimated in Ilus maum-r. ( Fi~. 6--7), is appr oximately 1.5 hr. A mort' acc urate met hod of t.'Stil1lalill~ tilt' half· lift, li st' S all tilt' datil ohtaillt't l durtng rlu- infusion. O n n.'arT'dllgi ll~ Eq . 11, Ollt' ohtains
0-3. Pi..... e.-............ ., .. (40 M./hrl fer 12 hr
T.~"
~I
hrl.. , ..... After.
c._...........1...
mA TMl'NT ()I 0.0.'.0.
C).mng mlu.sioo I
,,
, ",, o
10
33
s.a 70
87 93 90 95
PCJ:S/,nlu$ion
"
"
,o
0 .76 0 ,33
10
0 . 14
02
"0 '
i. 9
0'
- 0,1
00
71
CCt-.lSTANl-iATf if(;W,fNS
e.. -
CHAPTH o
Cinf _ C.. · e - k,
14
which upon l aki ll~ niltll r.ll lo~~a ri! l lI lis yn-kls
In Ie..
- C;n.1 =
In
e.. -
15
k· ,
tilt' tlt"'Clim' o blai llt"'ll 11)' p lultillg St'lll iluv;aritiullit~llly tilt' d ilTNt'lIn' hl'lWt'( '1l till' plateau conceru r auon and that at l'ar lit>T tunes a}!;aillSt tilt' l'orrt'sp'llltling lill ll' should he it str.Li}!;h t Jim' , TIlt' iIlI N l 't'pl a t till lt' zem is the- platt·au l'u lI("l' n l ra l iol\ (C.,> ami tlu- s1npl' is - k. TIll'S(' differences in conccntrauou SIIl1\\1 1 by vertknlHnes in Fig. 1}...7. urr- presented ill Ta blt' 6--3 ami haw la -cn p lutl l',t1 in Fi!-t. 6-8. Tln- dura illdi(.-a h' a Ilalr-Iife of 1.7 IlL It sho uld 1)(· I\utt-d that t h.· ]01I}!;l·r tilt' infusion, tilt' c1ost'r the conc ent ration is to tilt' plateau
11l11S,
value a nd til(' ~rt'lIIN is til(' error
i ll ti lt"
diITt'rt'lIt, - nu-asun-ment . G.·III·mll)'. d ilT<"r\' Ul ,,{'
values calculated frum ceneeutra tions ht")Ul 1d gO'}. uf the plat euu haw l'\l'tossi\l ' error. La st. tht' \,olt.lIlt' of distriliutfon is e,,,,k-ulah'tl kll0\\i T1!!: d ,>a"'IIIl't>and half.lift'; ill this C'll"t' it is III L. CUllsidt>r IInw tilt' concentration data at ami aflt'r tilt' end of Il.t' infusion. I'lolt i ll ~ t1 1t'st" dat a 0 11 s(>lIl il( ~aritl l1nk- pape f also ~\'t'S a st r.u~l l t li l1e , (m ill which half·life l,
The- \~-rtic".J 1ll11,..... "l'~'lIt tI... ,bIT,·n" ,......... -tl> " l~" ..~·"t r;. · li.." s ~ plot...-"u and ,oI ·" "I.I,,rill:( tI... lufu.j.. n.
_ _
40 mglh r -
o
4
_
10
8 6 4
2
o
Flit . ~_ S.·"'il"\>tMitlllnic- pl..t (If tl,,· .IiIT,-n-n...I_I l,,-twt..... pL.t,~"lt c.lm :( ..." ..~..,.tr"h..n lU>t1 !Iw " 1,....,,....1t1 nriult 11,(' inru,i"" """i n, t tim ... Als..
pl"tt...I",... tl..- , It·dini,,~ \'...t, .... of pL..\lIllt dn'Klu ., n'tll r" titltl (0) "'Pins! tiu.... , il,,1.
8
12 Hours
20
16
10 • (C.. - C) during infusion
5
o
C postmtuston
"f,,·, " ' 'I'I"nK 11,,- infu.
2 1
0.5
•
0.2 0.1
o
2
4
6 8 Hours
10
12
CHAPTH 0
C "C.. ' e - t ,
16
\\11t'U t !le~' diltilrt il'ub r {·'t
1'11('( '
Urine Data AJone If (t'ual dl'aralll,(' is cons tant. tht' mit' of t'X1'n'tinn is proportionul to tilt' plasmu couccntranou. Tlu-u excn-nou run- data can ht· tn'alt'tl in a manner anal ogollS 10 that of pla.slIlll data, ami t'st im alt 's can 1M.' made (If d im ina tion Ilalf-lift, and fr action t'wn'!t'tlundmngt'(l (f d . Au t'stimalt' offf' is ohl aiu t'(l at plalt'illl From
Fe _
11:0le 01excretion 01pla reou
Rote of infusion
17
!»t'('iIlN' lilt' rolli' of infusiou is t' llial to Iln- rolle (If d imin;t1inll, Fur example. wllt'll tilt' infusioll mtt' is -10 lIIWhr. tlu- ollM,,,,t'tl c scrcnon ran- at plateau for tilt' d nl g is 12 IllJ~/hr, so fi' is 0 .;3,
Plasma and Urine Data \\'i1lumt pLl.s lll'l data. values for volunn- o f t1istrihlltioll and c!t'ar,U1I"{' 1,lImnt II(' ('stim ;lt("(1. \\ 'lu-u hnl" pl.lsm a and uriur- dala an-obtained, renal clearuncc mu ll(' estnnan-d in add itioll to all 01 111'1' pharmat'okindit' 1>ilr.lll1t't t'rs . .\l on '(}\'(·r , a steady-slatt' experiment adlil" 't'(l \\ith t'u ustanl infllSio ll is 1111' pn'fl'm'tl method for ('stimating renal clearance. At plateau. al'(1lralt' ll\t"ilSU(('lI\t'nh ran II(' nmdl' nf Il(lth plol"ma coucentrauon and urine excretion ratr-. In tlu- p n 't'('tlilll-t t'xamplt , n -ua l clearance. obnuned by t1i\idin~ excret ion rate al plateau by C" , is 1.26 l Ai r.
STUDY PROBlEMS IAnswers to Study Problems ore in Appendix II,} I . Which 1 me or mon- of tilt' f(lllo\\ill~ statemen ts pt'rtaining to 1111lslant r ate infusion is 11Irrt1-1 :-' a . TIl1' tilll(' to n-ach a p!;ltt'au concentration depend s U I)llII lIlt' rate of infusion . h . :\ 11 dmgs I l a\i n~ tilt' Slllllt' ck-arano - reach tilt' SOUl I( ' platt'olll concentration when ~\'(' n at tilt' sanu- is , infusioll r ate. I', Dm~s \\i tll tht, ....uu e clearance J!;t'lll'mlly reach tht· plateau con centration at th(' sa me tim e , d . TIl{' ' U lll lll ll l of dm~ in tln- 11Ixly ut p lateau cannot he Ihl' sauu- wlu-n drugs wit h tlifTe n 'lll ck-umno- Valll('S an' infused itt the same rate . I ' . :\11 of lilt' al li In' . f. XOllt' of tilt' alllM', 2, For prt'lloll~t 'tl slI"";I,itl prt:lt1'lllln 'S, Slll'l.; nyld mlint· d llo ritll' is ~\'t'1I hy i.v. infusion for xustaim-d mu scle n-laxation. A typ ical initial dow is 20 IllR fnUnw('(! b)' continuous inru sion o f -I mWmiu. T Ilt' infusioll mllst II(' indi\itluali7.t'll lll'l.M dUSl.· or variatinu in thl' killd il'S of Illt'laho lism o f slIl'(; m -!t-holim' . Esti mate tilt' r-hmtnatlun half-li\'('s of suel'inyk-ho lint' in patu-nts rt'(luirilii lIAIllWlIlin alKI-I TlIWll1in, n 'sll('t1iwly', tn matutain 20 1Il ~ in tIlt' 11I1IIy,
.0
CON SIANT tATE
3. In
tilt" graphs on
11ll' fwd
p
~E GW,f NS
( F ig. 6-9) art'
'\\11 lIlutt ip l(. infusioll -mh'
S<.'t·II arlos.
Sketch IllI" untk-ipated phl-Slll
min. Xu!,, that lilt' tillll' scale is expn -sscd in half-lift' uuits. -I. D liriUl-t a n ill \·t"sti~ati ollal prt~mlll . till" calcium d lalllld hlud dng agell t Ilifl't )ip ilit· WllS infuS("{! at a constant mit' ( 1.5 mW'lT) via a n -ot al OSIllOtiC pum p Ihat a ll
a one-comp artmental modr-l.
, ..... 6-4. Nlfetllpl....I...... Dwrl....edel ......I. . . . Ite-Iy ..... With ...
Os."'.
I)"S. . .•
o
o
I
41
6
110 130 108
,1
14 5
75
no
10,5 I'
100 18 0 110 180
18 l'
15 16
110
71
17
, 1
18 ·-.:l ~ ~,C H
_ _ , I. do> ~,
oect>I.........,.,.,-.ody,.,._an"""""",,,,,,- ()",
IGJ
~
_ ~, P
fho,
~3Q6-4 0 1
ond e.._,DD Niedop ... .
_ ."'
1\l 84
a. C ak ulatt' tln- ck-ara uce-, half-lift", volunn- o f d istri hutioll , and .\tHT of till" t1m~ . h . Is lilt" app ru.u·h of tilt" conccntrauon til plalt"11I in 'l~n":'lIIt' n t wit h tilt' h.aIf-life o f mfedtplnc observed on rt"lI1o,ill~ tilt' infusion pump? c. If lilt" infu sioll rute- we n - 3.0 mW'1T inslt'ad llf 1.5 mgzhr. what would ht, till' expt'(1t..:1 concen trarious at I hr. 2 IJr, am i at plat eau? d . If the tlt'sin ' is to achk-ve till' plan-auconeent ratkm 'l~st )(: iah'l l with tilt' 3.0 IllWh r infusion rate instantly. what is thl' I ()adi ll ~ do<;t, rt'tlui rt'l l? 5. D ropertdol. a hlltyrnpllt'liont" dl' ri\"atin '. has 1.( '('11 IIM't1 for tln- preveunou and trea tmon t of U'Ub t'a aud \'1 )lJlit i ll~ ill po s tope rat ivt - pat it'llts anti in patients UlI\ lt'rgoi ll ~ dll'llIotlwmpy . Dropcndol is currently atlm iu i.~It'n"( 1 illtran'lIllllsly ami intramust:ubrly, I)( ltt. iU\1L'ih , ' procedures . 111(' oral r oute crea tes a p r oblem fill' path-nt s who are- murS('t11lS or \'(lIniti nJt. Gupta et n]. ( 1002 ) 1,,1illlalt'tl a 1'lllltilllluus-n ,lt';N ' n "(1al d nl )t. dt'l in ' I)' ' }"itt"1Il as a means o f , dt"lii~lt"(1 to dl'1iw'r d n')t at a constaut ratr- for IS Ill', iucompnrison \\1tll a 24 -111' coustant r ate i.v. infus ion. rate 0. 125 mW'lr. Tln- n -ct al
CQNSTANlAATE
CHAPTUO
,
~EGWo.E N 5
Dr.p.""" c._ • .,..tI
1. 6-5. M_.. PI
II
II.wl
I
M
the U. . . . . . . . . .1h .. lc. I. I I.ht I." Tlf./f lh,) Plasma
i.v. infmion
ConcenlrOlion 1l!1( 10 1 Img/U dev;ce
0 0 .5 2 4 6 8 10 14 18 24 26 28 30 0 OW, 80 2 60 250 250 270 270 2W 310 1,40067036 0 0
0 49 OW 183 1,84 193 152 1,43 1.63 0,65 02Q 0 .10
a. From til(' pla.'illla t'Ullt'('nt rlltiu n dill" aftN slo ppi ng till' i.v. Infusion, t-,;ti lllalt' tilt' r-linuuation half-lift, of
2
5
1.6
4
1.2
3
0.8
2
0.4
~ E
"2
·E
'"
0
g
C0
2
0
3
4
.~
~
O
.~
"
~ 0
5
0
2
3
4
5
2
3
4
5
~
u 0
0
2
<.>
5
~
E
~
1.6
/1.
4
1.2
3
0.8
2
0.4
I
0
0 0
I-l lt· 6-9·
1
2
3
4
5 0 Time (in halt-lives!
CHAPTU 6
12
fi . 1 1 "t1~m ft et d m ~.
ill. ('xp!n J"('(ltllt' r(·;...~ i h i li ty o f transc h-nnul t1e1i\'t' r) o f a new antidepressant rohpram . T allie fi....6 lists til(' meun l'J.l~ TT1a roltp nun <"ll llt 't' n l m t iu IIS ill six su bj ec ts
d u rilJ,i.:: and aftN a 24 -11 1' ap p!il'
Illilt l t ·
of "ilit'o ll(' adlu-sive-, d m~,
alltl .5'l isn p m pyl m)"ristal t>Oil u po lym er "a(·ki l1 ~. 111t' p atches (5 <:111 X 5 e m), ap plit,<1 In forea rm skin an-as . '",n ' covr-n-d fnr 2.J h r. All his lillie , the Il\1Ihs. TIl(' a\l.·rd~t· ck-arauce and IllIlf-lift· of rohpr.uu an ' SA 1.11.1' and 3 h r. rt· sI)('(1i \l.·I~· . , ...1. 6-6. M . . . . .11..-_ c..e.IIInrtI... Ihtn., ..... After 24.hr De.....1 Ap"nctlfl•• I. Six M.I. hltlects-
a. Cal('ub tt- tln- a\"( ·ra~t· mit" that robp ram is I lt' il1 ~ ahsnr llt"(l from the- patch la-tween 12 and 2-1 h r. h. Dt'l t' n llilw lilt' total amount uf r ohpnuu lIhsorlx'tl d llri ll~ the 2-I·h r applicat ion of IlIc'
patch.
c. Doc·.. lilt' appmad l 10 sh 'ad)" slalt' follow tlu- t'xlx'(1alioll of !,otl ill I llilif-Iifl', 75% ill 2: half-ljvr-s. am i so o n? If lint , hrid l)" d iS(1.lsS hnw the absorp t km-t ime - p r ofikI.
hr.
,.1t•• 6-7. T, ~ lhfl
o
P1a!>fflO dfug coeceenctoe Img/ll
o
1;,
54
75
9
65
70
46
12
20
15
0 .9
A dm /.: that d isplays one-compart ment ('t.aml1t'ri .slks was "d minislt'n'tl as a ll i.v. holus o f 2.')0 1II)!; followl'tl illllllt'tliatd y b)" a ('()!Isla nl infusion of 10 mwtlr for li lt" durutton nf a slud)", Estimate- the values o f \ 1 111ll11 t' of distribution. half· life . a nd clearance from 11ll' dut u in Tothl,· 6-1'),
t,me lhl) Plosrc drug ccoce-ecnce lmg/tl
~J .
34
6
03
50
50
98
76
40
In tlu - n-xt on Illl)!;c' 75. tilt' pract ical view of the a p pnllid l to plateau \ \ Nd-S pn-scuted. If tlu- tolerance at pla n-au Imd IX"(' 11 15%, instead of 10%. wha t wo uld lx, till' time . in Iialf-lin ·s, m-c-dedto reach this tolerance wln-n lilt' iniliill concentration is: a. S()~, of li lt' final (p lalt 'olll ) value h. ,' j( )( Y.f of lilt' final (p laleau ) valm-.
MULTIP LE -DOSE REGIMENS
OIJICTlVEI The reodet win be able 10: 1 Pfeaid the lote and eoeot of dllJg occurnubrion lor a 9'vefl regimen of fixed dose and filled
interval.
2 Develop a dosage reg,men hom lnowledge of the phaflTlQc¢l.inera and therapeutic window of a drug 3. Evoluale the liroetlO of 0 drug givet'\ in 0 mulriple-dose regimen IS EvalUOle the kinetic of a drug lo/b.ving 0 mvhlple-dos.e regImen 01 a conIToIIed-relea5oe lormula!lon 5 Det-~ phormocolo ,netiC palOI'l"'letet'~ for 0 dn9 from pIcumo cooceMotion lor weel dolo foIIov..,ng 0 rrulliple-dos.e regimen.
nit' p n lIlany (It
diaptN llt ·;,lt "itl. (UIl,t,IIII -r.lh· TI"l,'iIlll'U\.. \ !It.' Mlgl. till ·.....· fi"l,tiltll'lI' Ill"'1'" imhlt· ft..a tun-s. tht." an' II'" tiM" 111.,..1 (UlllIlHJIl nllt·... 1111' II M'n' ('tllllllMlIl "ppn",d l
iulls
In 11K' m aillh' llalK't" o f l"lm till lll MI'i 11 ... r.II~ h In ~\t. {"ll\l'~
11M'
lIIuhipl,· t1i\C.Tt '!l- tlo·... .... 111;" r-] t, lpll'T "IM·II Imlltipl"-o:I'N' n'1.,r;"ll'II'.
p !M nn;K"Ilkindil' printiplt·' .1"'(I(; ;Ift"ll ,ti th
DRUG ACCUMULATION I> m~ a n ' mu"t ('l l lll lllnll l~'
pn-scnlx-d to he l 'l~t ·1I 011 ;1 fiWt l d"w. fh."(llillw illll'nal ha~i~ :
" .~ .• Il KI III ~ Ihrt"(· finn-s a
of 'u lrHillhlr.llioll . Ih. · pl.l\lIl'1 IUll('t·nl r.llicm and ,11110 ' 1111 ill Ih t· botk 1I11l1l1ah- <111.1. ~ illl i lar 10 all i llli l~ ifl ll . ri,,' lowartl a
plateau.
.
Cou..id ,· r ti lt" sim p!"sl silna ticm o f a t1mag" rl'l.(inlt'lJ <"('II1IIO.)"l"( 1 o f " 'pla l
b"l ll ~
dust·s
ad lll j ll i ~INt"(1 illlm\l'lIl1usly a t fht"(1 a nd " ' Illal li llw illll 'n a k C lln .· ..\ of Fil.(. • - 1 ~11l1\\~ III1\\' amount ill tilt' 110. IO. k ,"ilrit·.. \\i ll. Ii Ill! ' \\"111'11 l\,dl t111~1' i ~ gi\( '11 ~ll('t' 's ~ h r-lv twio - , '\I'n
I.al f·l if(" Under 111t'....• <~ lIIdi l illll \ t l nJ~ ..,':IlIllIlI.Ilt'S ~lIh~lalllia lh ..\ n : lIl1lllb li.:ll l ll,, ·tl,... III:' (';J,1I'ot' dm ~ [rrnu pn'\inllS liu'lol"ll has nu l I.. x-u <'l ullpl"h ·ly rt ·Ill,~('( I .
MOlina ond MiaiJna 01 Accvm.lcrtiol lo tIM PlatfOtl Tu dpprt...-iate tilt' p ht'unlllt"ltllII of ,t<,\·UllIllb lio ll. t'llll~i.I, ·r \\ 1••11 11ol1'lIO.·m wlu-n a IO()' III~ hoI", du!io(' i.. gin'lI in lrd\t" MM ldy ' ''l'~ dimillalinll h.ll(·lilj·. 11... ;tl llo ' " lh ill Ill\' 1. 1I1~ jusl ;lflN (·oK·1J t ier;(' and jil'l I..-fon- Ih(' 111'\1
..
CHAPTEP7
(50 mJQ. 111\' amou nt rt' lll
Altt·m ali\'t>ly. tilt' value, i5 1llJ.:. 1lIi1)' simply 1)(' calcula ted hy n,(" ~ll il.i llj.( thai 1I1l1·· half of till' amu un! just afn-r tilt' St'(:Hm l dust" 150 1Il ~. remains at tln- (Oml of that dosillj.( Interval. Upo n n -!waf iuJ.:this p ml't'tlurt" it is n·"d i!y St '( ' 11 k lll'\'(' n, F ig. i - I ) that d m g uceumulution, ' ; t'\'l'(, 1 ill n-n ns (If ('itlll'r maximum or nummum amount in tlu- bodv. cont lruu-s lIu l il a
tilt·
li m il is n -ached. At rlu- limit. rlu- ,IIIIUllll! lost ill each 1111('1"\'<11 e-quals <1111011111 .I-:;lillt'tl . Ihl' duSt" I n thi s exa m ple, li lt' maxtmum und till" minimum amounts ill Iht' hod y al s t('ad~' stilll' an ' 200 1Il~ ami J(XI 1lIj,t, f('spt"t.1i\'..Jy . This m u st ht , ';0 sil l('(' rlu- d iITt' rt' Il('(' ht,tWt'('1I till" maximum a nd minim um amou nts is tlu- dost" 1U0 m g. urn ] sinn' a t tilt' (' nd o f tluinterval. Ollt ' half-lift', t he amount 1II1l., t behalf t lmt lit Ih t, llt-gin llillj,t. Fnl1O'\\i ng a constan t run- input, t !l t' I,l(l l nl/l is n-ao hed wln-u rOlf(' of t'li llliui(tio l1 lJlatdll's raft' of input. 1111'1l till' Il'n ,l of dm~ in lilt' lltltly is constant. With d ist:rt' f(' d o sin g. tln- lew! is not coustunt within a d os ing, Interval. b UI til(' \',(IUt's it! ; 1 ~n' n !iIIit' wi thin tilt' inte-rval art' t ilt' smm' fr om O llt' dos in~ interval to another, t hilt is, wlu-utln- umoun t Im l t'1lua ls tlnamount p;iliut'(! \\ i th in till' int t-rva]. 111t' term I,I(llnJU is also applied to tl.is illlt'n.losing
sn-udv-stan-condmon.
T1;(' ftm -going ('Ul\.sidl'mtiollS ran lit, {':qlillldt'(l for
t h t,
mo n - gt'lw ml sit uunon
i ll w h i(·h
a d r ug ts Wn'll at u t10 Shl g, interval, t . whit-h lIlay t1iITN fr om rlu- half-lift,. 111t' g,l' IlN a l t'(lliatiollS dt' n n '(! in Apl')('1II11\ I- E for t ilt' maximum a nd minimum amounts in l ilt' hody aft{'r rlu- Xtli tloS(' (As.,.....: ,\ ., .,....~ ) and at plah'llu (A .......: A ...."..) art' Moltimum amount in
• Dose -
body after Mh dcse, AN,.......
[II - ee--Nir] h
M inimum amount in
body oft8l" Mh dose, AN,min
•
2
Do..
w.oximum a mount in
body a t plateau, AIa. _
e
3
h
nil:. 7_1. 1)o ..i "R rn~ I IN'fK, ~ull ",l. th.· ", •• Kf'~'
ur drug ;((,(' lTl llll..lin n , e"I'\" ". 1"'. 1" >1,,.
(lUll "'10:1,..llIIiui. l,·n , 1 t",it~, ,.... . 1'\ halr· lir..; ( '(] 1'\1' " . ~11'" 1,,>11\, ,....... ...lmini',,,·n, 1
t ~ ...•
." "
l' n
f)
~1 ill
A
h..U·li f,·. ~ , ot,· llMt ti lt"· 1\ ,.\ -
l...If·lif.. unih
B
o
2
4 TimeIHall-lile
6
B
CHAPTEIl7
as
MUlT1f'tfOOSE IlfGW,fNS
M inimum c mcc nt in
A
body of p!ot8(lU, Au .""" -
.......... e
-h
-
A
..........
n -
_
UI:»e
4
R ('(.~d.1I From C ha p . :1 that the fUIl(.1 illll c - AI is lilt' [ruct ion of till' initial am ount n.> lJlaini n ~ in ti lt' bt ltil(" phenomenon of accumulation. l"llllsidt' r all oral dOSlI~t' n1.rj. Il W Il o f 0.1 1lIF; d,u ly uf d i¢ tn >;in . USl"l..1 in the t reatment o f certa in cardia c dysfuncnous. Althnu ~h not as \\itlel)' us("l..1 as th e mo re pop ular d rug. di~n'(i ll . di ¢tm in lIil'dy Illustrates lIIall)"o f the a~p("l...is of accumulation and d t'siK! I o f dosa~(' n.~ llwns . C,in>u tha t absorp nou is comph-te and , -irt ual ly instautuneous, o ral adm inistrutmn m il Ix' si111111<1.1 ("(1usi n~ is. ho lliS do S('s. 111(' a\'('nl~t> lmlf- lirt> o f d i ~ t mi n is 6 days : therefon-, Irmu E(I' 3 the maximum amount at plat eau is 0.9 2 1Il ~, arul fmm El l. -I the nrinunum amount alplalt'.1\1 is U.82 1Il~. Di Wtm.i1l <:It·'II'I)" . lIltl t> ~( I<'S considerable acc umulatinn when gin >1I dail~·. These calculations o f tilt' maximum andmtntmum \·ulut·s at plateau strili l)" apply only 10 intravascular IXllus udmlnistrutlon. Tll t>y an ' n-asonuhh- approximation s follo",;n~ extravascular adt ru nistrutton , when a hso rptiou is l~lInpl ('tt· an d ' i rtll:llIy Instantaneous. 11. t' fullo"in ~ discu ssion ch-als with a h-ss l'e strit1in > view o f accumulation , whi<:ll applies to ull routes of atl millislmtioll .
=
=
Awerag. Amount and (oft(fntration al Piateau
,l'
In lIlallY rt:'sIX'i-i s tilt" accumulatkru of drugs. admt ntsten-d in mulnpk- (1t )St*S is tilt" Slu m ' tll at observed follO\\-i nl?: a consta nt-ran - is . infus ion. TIlt" an> l'il~t> amount in the- h(l rtltI' j f l mu st equul a\1.> r.I~t · r ate out, TIlt" iln·r.t~e r an- in is F» D OM ·/t . 111t> U\ 'e rd~e nih> out is k: • A ....... wll('l'(>.-\....., is tlJ(' a\'t · m~t· amount o f d nl ~ in tilt" IXI
5
f · Dose
,
..
- cr . C
~
6
when- Cu ,... is the average pl.t'lllil rmux-n tru tton :11 lilt· plalt·al t . Sinl't· k = 0.69.1It 112' lt alst, follows that
..
A
7
~
and
F 00..
C......., - CL ' - ,-
8
TI J('S(>a re- fundamental I'd atio mhi ps; Ilw)" show ho-v til(" a\·e rJ.~l> amou nt ill till' htl
.
CHAPIH 7
sft·
D Ol~ accumulation 15 nut a plu-nonn-uon thai <1('1 '11.'11<1" t ill rlu- prupl.·rty of a tim)!:. flor are then' t1m~s that an' ('u lIllI Jatin' and utlwr.; that art' not. ..k (;lIll1u lalioll , in p articular till' extent of it. is a n -sult of tilt' frt'f IIWl\l'Y o f admini st rat io n n ·lalht' 10 halr· lift· lIit nr l/kt ) itS ShU\\11 in f'·i~s . i -I alltl '- 2 . :";olil't ' that tilt' anm l!!:l.' .11111111111 o f di~t()\j ll (O.Hi TII~). (';l!t-l l tlll't l [rom Ell_'j . Iil's mid" 1ly 1)('1\\'1'('11 tilt' maximum 0.92 mg am i tl.(· minimum n.s2 mg. Si ll ('(' m k ulati llg the aH 'mgt' valur- is lilt' uuu-h simpler p nl('(,-Iu rt" under these ci rcu mstances lilt' IIHlximUIII and mintmum ' ';IIIll'S (';11I t'a.~ily ht' (';Ileu b h'tl by "" 11.92 lIlJt: A ",. NO/ .. is O.S';' - I).OS '" n.S2 m!!:. T his simplt' uu-rhod is a n ';l'itlllahlt' appmxinumon us IUIl~ ux lilt' tlc" in!!: inn-rval dut's lIot t'M't't't I IIlt' half-lift,.
«
CornpariSOI of Maximum.. Awerage, and Minimum Amounts at P1oteou Fhutuution in lilt' amount of t1mg ill Iht· hUlly, like accumulation. ck-pe-nds on bul h In-, udnnntstrunon ami houf-Iift'. Flul'Iliation also depe-nds 011 ratr- of ah sorption;
1IIlt'IK.,.· of dnJ~
it is ~n';llt'sl for is . bolus adminislr.tlion . Fi ~l n' ';'- 2,\ illust rat es how nurdnuuu. mi nim um . and an'rd!!:l' amounts in tbt· IMxly at plate-an dqx'ml 011 lilt' fn 'tjllt ·' It)' o f i.v. IMIllIS adnunistratton . St'\'('m l nhSN \'illioTls art ' pertinent : ( I) TI lt'
A
5
B
5
4
4
3
3
2
2
~+.
"
.",
Average
o
o
o 1
2
3
Hatl-tife lOosjng Interval
4
o
1 2 3 Halt-litelOosing mterval
. " 11:. 7- 2. \ I"n ' fn~I''''' '1 ;oollll inht mh"" ....." Ih i" ;/, j!;n';4!t"r ("~n~'
4
17
CHAPTEP7
III·t·1I dilllillatc'(ll lI·fn rt· tilt' llt'xt dnst· is admuuste rcd . (3) Dt' fi nill~ Huct uanon as tlu- ratio . ..\ ..,.."'/ .\ ...."... ~n'll hy t ). · (Eq. -I). tln- ~n.'aI N tln- n-huiw fn.'(IIIt·II(.' · of admluistration ( II kt ) the s nud h-r is tilt' 1I 11l't tmtioll . FiWlrl' . -2 8 demonstrates how fluct uation ;11 plait-au dt'I)('lUb till fn.'(llIt·nt" of ad ministratio n. T he maximum ami m inimu m amou n ts an.' I·al·h ' 't:IIIlI'J;lrt.'(1 \\i th tilt' aH· ra~t· amollnt ill lilt' hody. S o h' th at til(' ;1\·t·TaJ!:I· is arit hll\('tk~.J ly d nst'r 10 tilt' minnnum th an to tilt' maximum value. This is part kul;lrly t"i de'lll for low fn'l IIWlldt'!> Ilf adm inistrat ion .
Rate of Accumulation to Plateau TIlt' ;\mOlIlII i n lilt' ht llly riws 011 mu ltiplt· dusill!o': ju st ilS it t1c)('s f(lllo\\in ~ a con staut -rate l.v. infus ion (C hap. 6 ). That is. tln- app roach to tilt' plateau depends 5(l1 l'1~' Oil ti lt· d m ~' s h"lf-lifc·. TI ll' clala fClr clihrilo'(in. in T ,\hlt' ';'-1 which shnw tht· ratio of the' minimu m amoun t d u rin~ \'arilllls t1osill~ Intervals 10 ti lt' 1II11'(iIllU Ill amount OIl plan-au. iIIuslm tt' thi s IlIlinl. O!.st'n 't· that it lak t·s I half-lift· (6 days ), or 6 t1OS(·s. In Ill' at .5()~' of the value at plateau. 2 half-li\'l's ( 12 d a~ 's ) . or 12 dost·s. to Ill' al ';'.')% of tilt" plateau vahie. ant! so 0 11. AI'l.·lIl'nul.llion of di~ IlJ'; i n takes a 10 1lJ!: tum- I)('(.·allst· of its Inll ~ h.llf-lift·. 111l' dt·~n.'(· of al.'l.·ullll llalilJl'l is t·\!c·I\Si\'l· . 11I'(.'all st· of rd ali\"t'!y fn.'(III('1I1 admi nistralioll . The frt"lII Il'1I1'y of achuinetrution al<;t) den-rmtucs lilt' small llu!1uatio!l in ti lt' ;111'I01 11I1 of dm~ ill th l' hody at plall'au: 0.1 Il'l~ is IlIsl t'\'('I)' dosin~ Interval, when then- is alllllli 0.9 1IlJ!: ill th e 11I1I1y. 1111' appm;lt'h til slt·ady 510111', ob<;t' n'('(1 for tilt' minimu m a moun ts o f di¢tosin in the IlIMJy, "I-'\(I holds true fur tilt' maximum (p mo f in Appc.'IJdi.\ I- D), and a\'t· r.t~c· amounts. Ihal is.
9
when- ' \,\
A«vmulation Index If tilt' amoun ts ut slt·ady sta h ' an ' comp an -dto till' l.'l)rn.'S!ltmdinJ' vuhu-s ut finn- t afh-r lilt' fin;1 dust ·, Ih(,11
10 Tl lI' IllIalLlily, I/( I - I' - h), is all index o f tilt' extent o f accamulatiou. Fur d i~ I ,,~dn (k "" 0.1 16 d..y - I. t "" I day). ti ll' (/("f'tmw!tlt ;oll indr x (n....) is 9 .2. 11l11s. t!l(· maxhnutu. a\l·ra~e·. allli mimuuun amounts (anti for tha i matter til(' amou nt at any ttnu- wit hin tilt' t10S irl~ intl 'n'al ;11 p1a!c'au ) arc' H.2 turn-s tilt' values at tln- u lrn.·l> lltllltlinJ' thnt·s 'Iftt·r u si ll~11' dust·.
'abl. 7-1 . Approech to PI...... _ Dally AtI.I.I.tratI_ .. DI.lto.l.. T'me (cioyl.l" Nymber 01 dosed M
[~~::~: :=~;] "
0
1 1
2 2
3 3
6 6
0
0 11
0 21
02Q
05
or plcreo"
"1...., do.
1,,,,_
· , ..... ~ ~ •• • l_ ~
, ".
12 12 0.75
18 18 0 875
2A 24
OQA
30 30 OQ7
,. ,. 1 00
II
CHAPTH l
Change in Regimen SUppOM' thai the decision is lUoult· tn helve till' amount flf di ~l oxill in lilt' IlCKly at plait-ail . 11('('(1 for a twofohl n -dnct ton in tlu- nth' of ad lllinistr.!linll. to n.n') IIIWday. f(lll(Jw~
nil '
(m ill
Eq. I .
As with i.v. infusion , it t ' IKt ·S I half-lift· to ~II HIIt··half till' way (m ill n,un to liAS 1llJ;{. 2 half-live-s 10 ~o three-quarters of tilt' way. and so nil . f or d i!,ritoxin it would lake about 12
days to go 75% of lilt' WOol)' to tht' 1lI;' W plateau. (TIlt' s.une prind plt· applit's to an i l1(:n ';Lw in tht, rolfe uf di~toxi Tl udmiuistrat iou.] TIll' Fastest war to :It:llil'\"[' 11.-15 II\~ wo uld he 10 d ist:uutinul' dm~ fo r I " 't''('11 (app mxill1ald y I half-Iifel lwfon- i llit iat i ll~ till ' rt'(IUl'\'(1 mil' of aduunistrution .
BIIATIONSHIP BETWEEN INITIAL AND MAINTENANCE DOSIS It miKhl Ill' I hl' r.J.p(·t1l kall~· dt'simhlt, to cs tahllsh till' n -quin -d amo unt of di~tm:ill ill til(' body on till' fi rst day. \\1ll'n tilt, first o r initial t1o~t' is in h 'lItleti to lit, tll('rajx 'util- It is referred to as tilt' " ti mllll!. o r lomlttll! dm(·. In this eot....-, tilt' patient would requi n - 0 .9 1lI~ i niliall~" followt'(l by 0 .1 1lI~ daily. For d i~t mj ll tilt, initial dust· ls often achmntsten-d in divided doses. St...e ral procedu res an' follo\\ '('(1, hut till' t1i\idt'(l duSt' is (111ll1ll11ll1y ~i\"(' 11 t"'"('I)' 6 1101I ~ unnl till' desirt'f.1therapeutic Tt'SponM' is obtained. In this \\~d)" t'al'h patient is lit rolh'(! III till' inilial tllt'mpt'lltk dost, n-quin-d. lustead of t1t·t l'nllin i ll~ the loadi ng; dost· wln-u tilt' mai nteuanee do st· is ~ \"(' n , il is IlIOl"(' (.'O Ill Ul UIl to dl'l t·nniut· tilt' mainlt·lIalll't.' dow «'ll" in'll 10 sustain a t1lt'rapt' lll k amount in tlu- body. Tlu- initial dost.· mp id ly ad lil...'e s the therapeutic response: subsequent do ....-s maintain tl a- rt-spun st.' by rt'plad n~ d n lp; lost du ring: tln- tlosillp; illtl'l'"tl. TIlt' manueuaucc dOM', D.v . therefore, is Ihe dtiference b etween tilt' In;u linp; dost·, V /.o alld IIn- amou nt 1"t,' lIlainillg at til(' end of tilt' d(Js ill ~ Interval , Di .
[~~ng
I'll -
e-
l
1
II
Likt...\i M·. if the mainlt' lI,III<-'" dost· is known. tilt' initial dtlst· can he es firuated: l00di109 do$9
.Maintenance dose -
fl
e- " )
12
Thus, for diwtoxin , a da ily mai nu-nance doS(' of 0.1 1Il~ requi res a le);ldin~ eloS(' nf 0.9 1lI ~ . nit' similarity ht'I\\1" '1I Eq s. 3 and II sho uld ht· 1I01t'(1. Frmu tlu- \it'\\' point o f l K " ' Imulatl ou. ECJ. 3 relat e s to tilt· maximum ,U IlOU Il I al plall';1II on St, f(·pt·t it i\"t·I~·. If the maxim um amount 'own' p nt into the hody in il iall~·. then ECI. II indica tes Ihl' dost· 1J("l,(!c"llto maintain that amount. n i l' n-lanouships ure tilt' SS) initially, follo\\1.'(1 1Iy 2.50 mg t...·(·I)· half.lift·, ;l~ she"'1.1 in Fi ~ . j -J. A tlnsa.gt· n '¢ lIlt'n l'( )lJsisti n~ of a priming duS(' t'(llIal tn ""it"· tilt, lll,eintt'!J;(II{'(' dus.(· alld
••
MUl III'tfOOSE lIEGME.NS
CHAPTER 7
rt·li!'H.'1,:lin'ly. Fo r d nl ~s wi th \"('1')' short 10 short half-lh "t"S. k-ss th an 3 hr. or wi th w ry long half.l in 's. !!rt'ah 'r th an 24 hr, this rt~ l1Ie ll is oftt'l\ Impractical, Aitholll!h a load illl! or initial dn.\(' !!rt'i\tN than tilt' mumtenauce dosl' seems ilp pmp riah' for tlm.gs \\i th half·lives lonKe r than 24 hr. such is often 1I0t th e l-.L\t.'. There art' il varid y of n'
MAINTENANCE Of ORUG IN TNE TNERAPEUTIC RANGE J)OS
HaH-lives Less Than 30 Min C reat di llklllt~· is l' lll~ )II n tt'rt'1 ! in tl')ill~ to maintain tlu-rapeuttc con cem runons nf lillt'h dm.gs. Tlu s is pa rt il"tI la rl~' true fllr a d m .g with a low therapeutic Index. t'.~ .• ln-parin. which h,lS a half·lifl' o f app m xilllilh 'ly 3() min. Sm.- h it d m ~ must hI:' d tllt' r tnfuscd or t1i S(~lrt ll'll uull'lis tnn-nntuent concvntrut ions are pernussihh-. DmJ.,'S with a hiWI the rapeutic ludex 11m)' lx- ~w n It'sS Ire-que-ntlv, bill till' ~n'ilt N tln- dosin~ illlt,,,,"..I, th e ~rt'ah' r is lilt' main!t' nallt'l' dos(' n-qnin-dto ensure that drug in the hody stays above a minimum I'lTt'l1i\'I' \'alllt,. I't'nidll ill is a notahh- example o f a dr ug for which till' dosing interval (4 10 fi Ilr ) is mallYtillll's l"lI~N than its half-lift' (app rm imatd y 3() min ). 111t' t1ti'>t' ~wn ~rt'al l)' ('U1'l'l!S that rt'1 luirt'1l to ~idtl phsma conccutrnttons of antihiut il" 1'1 ll1i\'alt'nt to tilt' mluimum inhihil ol')' (111It'l'ntmtioll for most mlt'm o rxani sllls.
Half-lives 8etwftn 30 Min and 8 Hr Fo r sud l d m gli. tilt' llliljor t'1 ll\Sitll'riltiolls an ' tln-rape -utk- index am ! t'l)lln' nil'nt1' of dosin.g. A ( Im~ \\1111 a hi.gh tlwrapl·ul i(." intll'x llt'l,(! only II{' administe-red (IIlt't.' 1...·1·1)· J to 3 halfli\'l's. or 1' \'1'11 It'sS frt'q llt'ntly. A t1mg \\i tll a low t1w rapt.'u tic index IIII1St I'M' ~\"t' ll appr ocIllat t'!~· l'H'l")' hal f.lift', o r uron- In-quently. or be WH'n h~' Iufuston. Lidocaine, fur examph-,
500
~
.~
t·i~. 7...1 . Sl", ld, (If Ih., am'M,,,t nf 111r.lo(;'·' dill" in II... I• • ~' Ii " ... ; . 1" ", 1,&1;'", " f II" , t \ '. ...lmini, lr..linll ur SC MI Ill1/: illill."l1... ;tiM! 2.'50
"" ,l.
A
"e
~C;
E ;;; -
~
~
0 ~ 0
250
B
-'"
. 0 0
0
"'If ,'\...~. " I,r 11,,·n·..!t,·,. ('(.,,~' A. \\1"'" ,I"· ;u"1 " loIi nh ·I.... M.... I],...-s .In· II..· '"Ill" ' , ll. il taL.,. "Pf' nn.i ""'tl·I~· .10 I,r (3 I" 4
j" il i
h..Jf·l"•.,.\ ".·f" .... II... p1;oto-;ou i~ r r....1 it·..JI~, n-..d "~1. n "·n·aft,·r. ('1 ,,,.....\ ;0".1 K ;on' I'''''''· 1i..1" tl,.. ...."....
0 -
E
0 0
8
16 Hours
24
32
90
CHAPIH 7
has a half· life of 90 min, and the mngt' of plasm a couccntr auons asso ciated with tilt" treat "W ilt of ca rdiac arrh~1 Iun ia... is on1)" a),o ut thn -efold. Thi s d nl ~ must he.' ¢WII by Infusion to ensure pm]oll gl'(! supp ression of arrh~1 111 11 i;L" undmmtmal tox ic.."ity.
HaH-Uves BetwHft 8 and 24 Hr Here. t ill ' most convenien t and dt'simhll' n~ IlWIl is o m' in wt.kh a close is ~\"l"1I ('\'('1')' Imlf.li fc . If im media te achievement o f steady stan- is des m -d, t1WIl. a.'; prt'\; ulIsly mentioned. the iniH,l! dose must he twice the maiuteuauce spt't1:i\'t'ly.
HaK-U·. .. Grea'er Than 24 Hr For drugs \\;111 half-lin 's greater than I <1.<1)', administ ra tion (lillO(' lIai])'" is (''Il n n ' n it'n l and promote s paUl'lIt ccmphance. If all inlllll'tliah' the rapeutic d Tt't1 is dt-sir('t l, a tln-rape-uttc dose neetls to he ~\l'n init ially. Ot lit'n\ist' th e initial and lIlai nteuallt"t' do~'s ;lrt't l.c sallie , in which case several doses Illay Ill,' Ilt'<.'t'ssal)' lx-fon- the dnl~ uccu nmlates to tllt'mpt'uti c levels. n it' decision whether or not to WH' la~I'r initial t\Ost'S is oftl' n a pract ical matter. Side t'fft'<.:ts to large o ral doses (ga.\ tru illft's ti nal side efft 't1 s) or to acute-ly hi~1t couce-utration s of dmg in tln- bOlly may I\('t'('ssitate a slow accumulation. '."•• 7-2. De.., • •.,1........ c..tI._•• M.I..._IIC •
., "'-,..tic e-............ ""WI"",
""'" floed'um fQ
R.A.TOCf NT\OJ.
..ro os
oose """'""'"
I'oIT!:r.tAl.1Q
"""'0 HAl.Hf!
OOSNO
"-"'U,
Gf:I\lRAI. CCWME NlS
Dl1VG !w.¥Us
Nolfogtveefln
3-<>
Ccrdcce lor com.fQnl-fO!e odmmis/l'ollOn ond/or lhorHe<m lheIt!fy high lhe
<30 mIn
High 30mmlOJh,
1-3
8-24 hf
1-2 2
>24h.
>2
3-8 hr
1
Cephalo,.porl~
Tetracycl,,'\& V~ommon cod ifObie 'eglmen. Once dolly ;$~oct>c.oL Occcececr gIven once
weeUy, or leu I,eq,*,~ , mc.Jyneed
IMIO!
ceee
Sulfamerhoxozole ChloroqUIne Iwppre»ion malario)
aI
fQ be much glea!el !han ma'""
eocec e dose <30 min
No! 0 callClidare excepl
Nllfop'u»ide
011." by ,nfu$i()ll
l idocome
11~6$ 3-6 OO!l6$ pel . bulle» Irequenlly
Theophyll,ne
"""" ;;;r do,"" conlfol infu$iOl\.
30 min to 3 h,
J-8 h,
1-2
- 1
...., conlfolled-releo!lot! IormvlatlOO
8-24 hi
2-' >2
>241'1f
......
~","""
............ _
0.5- 1 <1
............... tlooo/"""'~ " ... ....ooce doM ""'"' doug> ......
~.
C1a....d,rwl' l1equile$cOleful conlfal. once fQxl('Iy ;$ peodcced drugcooceeeosce cod IQxic'lydeclu-.e ~
..-.. ............. _"'0 <> io<Jd,r,g doM doooogo ..
0'9 'IO><,n
1"""'......... __ """ .... - . I ____ .,
.,
MUTIPLEOOSE RfGINfNS
Tn summa rize l ilt' fnn~(Jin~ di scu ssion . ccusklc r tilt' a ntihiotie dm ~ te tracycline, tilt' nasal l"tlllgt'sta ni pllt'nylpmpiulnlamillt', and tilt' an tu-pilept je agt"111 plwnobarbital , a nd Iln-ir dusa~t· rt""Il'IIS ~hl 'l l in Tahlt, 7-3. Jjsle
or
Dow 1
Tillw (I.,.)
2
H+
, 0
A ...__ 30
...\ ...nW~
( III).::)
7.S
37.5
lfi IH
.1
( 111~)
9 .4 39 ,4
By tilt' third doS(' (24 hr]. tllt' plalt'au is virtually achteved. IX'i n ~ gin'lI en'l')' h \1I half-lives. tilt' acoumulanon o f pll('nylpm p;lnolamillt ' is minimal. Fi~lI n' i -l is a sketch o f tlu-a mounts of pllt'nylpmp,lIltllmu illt' in lilt' hellly wit h
500 30 30
tunc.
8 8 8
250 30 30
8 4
100
, ...1.7-4. A••••• ef D-. I. a.4y 1.,1 ..... 1. . . . 01••• 1. , ...1. 7-3 ' fACTION
.",....,
""'" ~11rle
prop:mohn,roe
Pbeoobo.buc! oc;.- t>,- .. .. -I
.:~
" ,.Ow.
Af H'() Of ..-mfa,/.'
05 025 0901.6 ' ··O..,l1 - ..
'~
~"'~_-I·O",
"''o'f 9.AGf: "'I SIEADY ST"'TE&
""""'"" '"""
"....,.,,,
SlAtE'
ST ATE~
360
500
40
250 10
556
526
22
540
'"""
CHAPTER 7
92
TIlt' s anu- dosagl' n -gill1('l1 fur pl lt'llol l6 m~) and the Imlf.li ft" it is appan'lIl Ihat a sk,·td l mu st lit, '0(;,,1('(1to fiOO mg and to aho ut 15 dl.'~"S (Fig. j .....') . The cu rve is sim ilar to thalohlaillt'i.l \\i ll . constantrate Infuslou . 111t' a mo unts in th e bodv a l IOU hr Is 1I11l·-ha lf Hf till' stl'ild"-sfll!t' amount. and at 200 hr the lew" is 75% o f the piatt'au amount. alid ~ ) 1111. Pr.l(:timJi~·. t !tNt > is Iiltl,' IWt"(! to coushk-r tilt" min or lIUl1uations. Tilt, clinical imp lications or tllt'St.' n 1.rim t'lIS art' manifold. TIlt' ft>lrilt,,·litw rcgtnwn is dt'siJtIl{"(l lo uttuiu and lIIainlainlllt'rltpt'nl k levels. The pht'llylpmpa nolamint, rcgtmen W"t:s rtse to la"Rc flllduat iolls that may lit,
t"l,it. 7-4 . s1;c,.>/;t,ni'''· in thi' ".J:.' 'nt h ti,",,;
40 30
20 10
o
tllC . 7-5.
Sl.·td, " f II... ;l.In''' 1ll1 Ilf
'''' tI
t . 1.....1).' ~t .. I...
5.">6 allI l :'S2fi n,~
;u't"
8
16 24 Hours
32
40
60Il
p1..·,,,.t>;cr .
hit;d i ll II..• IM"I;o-' with lim..; .i m "t.t~ I" ,of :)II lUI( ~ n I» , ,,,,.. .,'!l hr. JWoooOl... II... l~df·bf.·. 4 '~'" P tn·,",,·J:.· 1<"'1: .... 61i>.. til II ..•
o
SIe-'dy·stale Values: -
~1I""1'
ri J,(l ll.
0200
I
' 00
o >----------~ o 5 10 15
C HAPIEIl 7
barbitaltln- appmpriale n '¢ I1 U'lI depends 011 whether tile drug is 1I!it'(1 for sedation tIT "-'_ ,ml it·p ilt·pl k-. Fo r !it'(!.ttioll. tln- o missio n u f a loadi ll ~ do·....is rk-sirahh-, ill that lolt'r-IIl(, ' til till" !it'(I.ltin- d Tt'("! dt·w lops wil h lilll P ;Uld a laTgt· priming doS(·. finn mg. (-.III'WS 10 0 ~Tt'a l a cent ral dep n 'ss in' t·ITt'(.1 . As an alll it1lilt·pti c. howe wr. a hltling tluS(' may Ix' appropriate. A lt l u lll~h IlTt'\illllSly pn-scnbcd as such. chronic administmtillll u f pheuobarhital tim",' ti lllt' S dailv is IlIl Jl( '(.'t · s.', ar\"; OI K't· dallv administrat ion mav lead 10 la-tt er 1:1I
La{·k of « nnpltaucc is a major problem ill pharmacotherapy. l1 w 1II0si Fn-queut patten! o f nOllu lmpliau l,(' is till' tlt.'t~l-siu llal omitt ed d nS{' or fajllln' lo ta ke several lUIl'i.('(.·u tin' do!it'S. Ht"¢Tl1t'lIs " f multiple daily d n"t·s teml to p n klu{'(' lUt'a ter frequencies of missed duS('s than th oM' ill whi<'h a d mg is taken (l m't ' o r twice daily. However. dt'(.· n';l-sing Ihl' fn'1IIlt'IIl)' u f dosillg: (with lurn 'spo lltliug: inl'n ',l-\(' in ('ae ll dose) lIlay not improve Illt' matntenance o f l"Olln'llt ratio ns wirlnu th t, d Tl'(1 i\"(' range. 111t' impad o f it missed doS(' is sho\\11 ill F ig:. 7-fi fo r Tt'¢ mt'n s of 30()' 1llg: (JJl('(' daily and WO.mg ('\ ·t·!) · Ii h r. In hot h n '¢mt'lIs tilt, total dai ly dose is tilt' same. O mis.sioll of it .single (l uly 30()· mg dose produce s a much 10wN min imum concent ra tiuu than omission of a l{){)·mg dose for twn reasons. First, til(' amount lost d uring:till' If)n~N lnterv a l (If tilt' fomu-r r~ II1I 'n is gn ·ull'T. Second. t he aW rdgl' millimum couccntranou a t ste ady sta te is lowe r for li lt' n!l{'(' d,uly n '¢mt'u . Thus. omitting: a s i n~lt' tinS(' du ring: a U ll(~ ' (bily n-gtnu-n lIlay ha\'t' a much g n'atl'T Impact o n therapeuttc n ·spol\St· than oTJlilli ng:an 1'l-1lOurly dOM.'. :"0:(111' I hat ('\l'1I omitt ing t 11Tt'(, consecut iw' doses of the g· lulIl rly n "¢lI1t'JI (the t'1luivalt'n l of a m w(·.t1.lily
A
B
20
20
~
~
E 15
~ 15
<£
~
,g
0
~ ~
11
€ 10
10
~
0
0
u
~
E ~
,, ,
~
0
~
u
~
5
E ~
i1.
5
-"
c,
0
0 0
24
48
72
Hours
0
24
48
72
Hours
1'1.11;.7-6. FrUin ~ kill il: pc·i"'pc..·h..... tI,,· lr"f"l'-1 "f a ",l~.. -d .t....... \.s 1/:n -.d. ·, 11..· L..1):t·r II... d....• ""ltl l h.· 1..",. fn'(I''' '''1 tI..· ...1",illi,I tl lt..,. <:'..".i,I. ·, . h·.. ly.•tah· mlllti..J....• ('o ' Klilio m r...... . In'1I: with a 11..•....I'.."tit-...il ltlo-....· "f 7 I" 2n II,(fI. (....m ..-n..·,..'(11. .. ,,~ " "' •• "f .L.l rih" Ii.." of 2.1, I I ~ ilIltl a ',:.df·lif,' cof 1.5.9 11f, PlUM'1 A: Who'll " .1111)." " 1/: , 10- ..... i . ~ •." "'K~' tlaily' I" mainlai" th,·ntpt ·"tit- '~" K~·lI t 1'lttic ..u . a "' i......J Jo.... n.. ull ~ ill • t"'''1I:1. I....' · ("(·" I.-.tl ic", "f2.5 mw l ~" ,..1,......d l l...·I0-'" tilt· Ie",, ·, li",it " r t l..• tht " Iit- wi'.. " , P. ....I Ii: \\ l "'n a 11X1·n,!>: , 10- .... i. l,'i"'n ......1)' " h. (•• .I.. " ..I Ie"'1I; .LuIM ..I Ii".·). tI..· 1e.........11'Ot ·lll ntlic..' ·hic 1art.·, a lJ ,,~' mi. .. .. 1.1,.... i. 7,:}"'!VI.. a ,.:.d"•• " 111"" II... 1I"' '''' I'''"Iil: , u K..." I....lic", ''''!t'-". If 3 ", ,Ii • .Ic "'" "'i •....! (o...Ie,,...I ,I>,,rt. ,Lt.,IIt..1hn.·)11... mi" i",,,,,, n KK.·n l r-..Ii,.., <3.7 mii',il.) is -.till .,}M • that ,>1 ·"' 1 "t..·" a .'''d<- .Luly.Ie...• "f .100. fIll: i. "'i. .... I. TI,,· ~~lrt · " * Lph..1 fnll" ........ p.......,I I I':,'o· 1£0')-' G.• A pllitn'lO. ..oIl I1I>1i..' •. ct., 11"'" " .....1. ",..,. ,54:U2·W. IW.) .
'11.
••
CHAPTER7
by olin' daily dm i ll~ is ("OUlIlt' rt't ! hy kim'fic \\ 'hen- tilt" opunnun rt WIIII' Jj lit·s
ill l 'n 'il '>t't!
pmhab ilil)'
o f l'tlllJ p lia u l'l'
a'Xu ITlt'1I1s in f
lilwliholJd of ("Il1lip lia lJl ,('
(M'n 'n t)' illlt i llillu rt·
of di M':L""' , oceu panon ( If path-ut. !It 'NlIlill ily
of p;i1ient ) am i t!lOSt' rt' lal in~ to tilt" pll
PRACTICAL ASPECTS OF MUlT IPlE·OOSE AOMINISTRATION So far, {"f)n.sidt'ratioll Illl\ lx-eu J'iH'n p rimarily to ti lt' amount lIf drug ill tilt' hody follo\\in~ mult iple l.v . ho lu" iuje-ct ions , o r tln-ir equivale-nt. at ("l itlally s!l;l{'t"'l.1 intervals. In p r act ice, ch n mk- ad ministm.tioll Is usually hy till' o ml route. Furthr-rmon-, 1I11ly d nl ~ couccut rauon in plasma or in blood r-an Ill' measun-d and not amou nt of d nl ~ in tilt' Ixxly. T Ilt,st,
btrIYascvlar Administration Tln- oral (also iut rumuscular [Lm.]. lnucai. SIIIIt:'lItalll'tlll\ [s.c.], and rt'l·tal ) utiministra tillll of d nl~ n-qulres an add('t.1 stt'p , «leorpnon. 1-:'1\ ' I to -I appl~' to t·xtr.l\·;l'>('ular administrunon, pnJ\idl'
rt'Spt't.·lin·I~·, 111{, sltMl)t'ss
(If dn l~ absorpttou alTt't.i s lilt' dt·,gn 't· uf lInl1l1atinn around. hilt va hlt' of. til(' avt' mV;t' {'llll(...-ntration. T Ilt' t'xt" ptiun is \\'11t'1i ah"u rpt inl\ Ix'('u l!wS so ~ 1(Jw rhat then- is illslllTk it'nt ttnu- for comph-te abso rption. (' .V; .• wln-n !imi!t"ll hy tilt' transit tim t· within tht' ~;l,tru i nh's t i l lill trotti , 111(' dlt' mpt-'util' imll;l<1 of
l i lt'
Plasma Concentration VHSUS Amounl in Body Dll ri u~ ltIultiplt· dnsiuv;. tilt' p l:l\ll\ ll ('()Jlt't·lltr.ttlnl\ (~m lx ' t~\I('lI l a h't l at allY tilllt· hy d i\i din v; tilt' (,( ,m'S pollt li n~ t"lluatiom dt'fi n i n~ amollllt IIY\ul ulllt' Ilf di,t rihlltillll. I>j"trihlllion t'tillilihri ullI Ix·t"'t't·n d m~ in ti lt' ti"SUt·s ;tIld tlMt ill p1:tsma 1"I(('s tilllt', T hu s. ob st·l"\'(·d m;l\i rnmn n lllt'('ntrd!iollS ma,. ht, app n't.·iah ly ,gn 'alt-r lhan t! UN ' (1tlt·lIl..h't l hy d i\ idi ll ~ E(ls. I 1111113 hy \ ' ( St 't' C hap. 19), 111t' a\"t.· m~l' pl.tlt·,ltl t, mn'ntralioll 11m,. hi' (·;tlt-lIlah 'l l llsin,g Ell' ~ . 'n .is t'(ltl;t1ioll is ilpplit'ilblt· to any ",lItt'. IIlt't llllt:l u f iltim illistmt iuli . or t lt lS;l~t· form , 1l\ I,," l.: ilS h ioa\1lilahilily illltl dt·ar.tlJt'(· rt'lIlaiu ('(lIlst;mt wid l Ixltll tilllt· and dust,.
.s
CHAPTER7
DESIGN Of DOSAGE REGIMENS fROM PLASMA CONCENTRATIONS (). )s,,~t· n '¢IlIt' Ii S {'; 111 lit' desiWIt't1to maintain ceuneru rutlons wtthm a tht ·mpt·lIlic window. TIl(' \\i lldnw is dl' filll'ti hy a IOWt' f limit (C" .........) and an upIX'r limil (C ..,,,..... ). TIlt" maximum d()si ll ~ int e-rval. T"..... and maximum maintenance dns('. V\I ,"""" ran he n'ad ily computed frn m tln-se- limits llS follow..:
13 whe-n - 1:""" is lilt' maximum lime Inn-rcul ove r which tl w~' Ilppt'r and IO\ \'t"f conccntruuons cnn oc cu r. By n'arr:Ill~I'IlI(' 1l 1 of Eq. 13. ti lt' value of T.-. is
14
and. Imm 11\l' rdaliollShip. k ::: Cl ,69.V t 1l2 , 15 TIlt' n ) rn'sp0l1(li ll~ maximum mainlemlllt't' dose, D \I,,,,,,,. , tha t can 1)(' ¢\'(' II
('\'(' 1) '
T""". is
16
C....,I
\ \ 1)('11 J).\ /.""" . is. ad1l1i nis.tt' n'(l t " l ' f)' T...... , then- ts au a\"l' rJ.~l' n Jll('('ulmlioll pmdut't'tl \\i lh in till' dosillJ.: interval . t1I' l111t'tl by
17
10
10
10
8
8
8
2- 6
6
6
•
•
•
2
2
2
.,;, oE
~~
~, 0 " "
~ ~ 0
0
u
0
0 0
6
12
18
2'
0 0
6
12 Hours
Hours
18
2'
0
6 Hours
. 'i ll:' 7_7. D,ll.·r.·'....... in tl..· . 1"'''1>1;'''' r..t,... I..'tvo...·" tv." ,L J.," · f" n,.... ~·r.." '(I Il<'n· f"f ;1I11,tr..t;" . ' purp",... . f"lI',"; Il~ a 'i"~'" ."tr..,a,nIL.. ,L"... (\" ft 1"',..·1) "Ill I · It m..;".. ,1..·....I..·utk· i" 'I_i ..t pl..t...."
l."
.
CHAPTE R?
By d i\i ding Eq . 16 by E'I' 14 and (,o lllpa rinv; this ratio tn Efl. I i . it is appan'n l tbu t t11('
vahn- of C.._ Is ~\1.'1l hy 18 A dfJSllgt· nWIlIl'1l ma), be.' dl'silQlt't) hy Slotting ti ll' d ll~ i ll V; mIl' ('itllt'l' lu ad.it'\1· tilt" average conce ntranon . C.. AI • or to maintai n a pl.," k concentranon. In IXlth approaches . couce nt rat tous an:' maintained wi thin th e tlw mpl'lI til' window thruuV;holll tilt' dos illV; interval.
Maintenance of an Average Concentration Choosing ti lt' a\'t'rdv;e conce ntration within tht' dosing inten..,,1 at plan-au 10 bt· C...... allows till' grt'ak sl possible dosi ng Interval. This dosing interval (Ell. 15 ) and tilt" ('()rrespond ing
tnalnteuauce dose.' IEq. 16 ) mil)' nol Ill' practi cal. howeve r. Bot h values ilia)'
II( '('()
to be
atljllsh"l:! to llIalt· the fn"({'lt"lll) ' (If administm tion coowment for pat il'llt (1)m p limlt1' and 10 accommodate tilt' tk)S(· strengt hs o f the dnl ~ p roduct s available. TIl(> ~llid i ll~ prt uciph-
is lu maintain tlu' sa me rate of admt ulstrattou am i tllt'n ·fon · tilt' same chosen a\'(' rd~t' steil
ami the l(}i\(lin~ dose, appmpriatt' to attai n the stl'ady-statl' concvntrunon, initially, is
20 If mo n - (or If'ss) \igomllS Illf'ra py is desi red. res lllt i ll~ in the st' U i ll~ o f tln- an'ra~l' largt·h·d conccn tratlou 10 lx- highl' r (or lower) than Cu .... ' till' d()si n ~ rate canbe increased (o r decreased ) pro pcrttonatcly. However, one may wtsh to adj ust till' dosiJlK illte r'\'ul to l·I1SUn.· that concentrations remai n within the t1lt'mpl'utic wtudow.
MaillttfKlMe of a Peak CHc:entrRtton TIlt' second approadl 10 till' design o f dOsagl' rt1Q lIIl'lIS is based on tln- IIt'sin' 10 maintain a gi\1.' U p -ak conceutruhon . 1111' pe-ak concenrratton chosen . C,....I. depcuds 011 how aggn'Ssiwly Oil(' wishe s 10 PUrsllf ' therapy bul usually ltes in till' upP"'r ha lf o f till' t lu-rapeutie wi ndo w , The maxtmum dos ing Interval is:
MoJilim um dosi ng interval -
I'IC.,../C....,I
k
21
O n d lllosing a conwment Interval. r . less than tilt, maxi mum dt'fill('! ill EfJ- 21. ti lt' mainn-uance dost· the n be comes
anti till' loading dust" if nl":t' sSUI)', is \ ' . C,.....l. Note thai C,ond is tilt' same a.<; C met hod o f rtOWlllt'1l dl'siRll It·mL.. III 1)(· snupler than the p n...-ious om-.
This
CHAl'TEIl 7
97
For t-', amplt" lunsit!t'r a t!m~ wi th a tln-rapentte window uf 2- lCJ IIl WL. a \u IUIIW o f di slrihutioll of 2.'i L and a lfi-hr llalf-Iift-' (k = (J.04.3 lJr - I ), 111t' maximum dosin/;t Interva l is 111t'1I .37 hr li n (l O/'2 j,1I.04:l 11r - I), If an Interval of 1:2 hr is c hosen. tIlt' mutnten ance d uS(' llt'l'llt"'ll is then ahollt lCJ(J 1Il ~ ( \ ' . C,.....I(I - t· - lr TIll' load ing duS(' (V . C,,,,,,, ) is 2S0 lJl~. If till' rq ;lIlt'n is dl' si!{lll"'l l llll till' hilsis of alt ai n i n~ and lll ai Jllainin ~ the a\1'rll~e ('( JIIrr -nt rution , till' maiun-uauce doS(' (Eq s. l"j and 19) is then 6.'5 1lI~ and till' l ()ll(lin ~ dose (EcI_ :20) is !fi(J 1l1 ~. F i~ lrl' 7...), Illust rates 11](' dilTt'n·Tl(.'l'S ill tlll'5e two approaches . Following r-xtr avascnla r adnuuistrutjon, fluduatioll5 in till' plasma eonrentra ticu of dnl~ an - II'ss thun thost' aft e r iutravuscular admi nistratio n. Dqx"lltlill ~ 011 ti ll' slo\\Tll'ss nf rhl' absorption prlJl 't ' s .S, it lIlay Ill' !'lt lSSihll" III adminislt'r tilt' dn'g II";;s fn"'ll' ll'lIlly th an lmhran-d in IllI' rl~lI1t 'ns dt 's i~lt "'l l by I'itl ll'r of 11ll' last two 1l11't1I()(ls.
».
W1tea
BioGvG~abili1y
and Volume Are Unbow.
Orul t1llSllgl' rq..ri l111'll S 1~1Il " ISl l Ill' 1 II'si~ Il"'l 1 \\i tho llt ddl'nnining bi ();I\'li labi li~·, Thi s is accomplislu-d usilLg tilt' an-a nnder lilt' plasma comvm mnon-ttnw l'U1YI' (AVC) fnllu",inR a singlt, d osl'. From th e n-lationslup F ' Dose = C I. ' A l!C after a si ll ~l e duS(' (Eq. 7, C hap. 4) anti tilt' rt,latilillship F . D llStvt = CI. ' C...... du rinR slt'ady stall' lIftt'r Illultipll' dost's (Eq. 6 ), it follnw.. thai
C• . L..-_ _- "
AUC (single dosel/f
...
~ ':..-__'_..;...-"-
Loading A B
Upper Limit
10
~---- -- - --- -~-- - - - - - -- - -~- - - - - - -- - - -
" ,B
"
8
,, " ,
,
II
,
I
" , ', '
A
6
I I I I
' ,,
,' " , ""
,
I
"
I "
r,
250
, ,
23
Dose Maintenance A B
., , ,
200
"
,
, -,
I I
"
" ..'
"
-, ,
",
150
0;
.sE
1
~
0
E
100 -c
4 Lower Limit 2
50
o
o
o
24
12
!
36
Hours . 'il/:. 7-'1, I),jT""·'M1~ in N t> UI.1'"xl. n( .101'Wl..... n,.;nx-n ,Io~i!:lI. Il''!:ill w n ..\ b n li< I I>I. d :. lmd 10 .Io-ri~II ..I I" m.<.inlaill 1111' "'''11' .,,'r"l:" 1111111·nlral"", ;o., Ilw "I>I.<.i'1I11 "~II'n II... ~1"1I" "lnati ,....\ J....rr (2 IIIWU Ii'nih It ' '''nll·'' It ((. >I. .r...1 ~tipplo..lli'll' ) i, c lo~ilQ ....1 In ,·u'u ", dUl II ..• p"a~ ('"'I1>lI1r.tllll' ,10,,·. Ill" ,·.........1110.· Ul'pl·' limit . Of l'''I"''' , a 10....·, ,..."" _-..)'11' n...~· I",,," ""'" d ..... ·n, Tht·Ic.. I; n~ ,10..... " "lui"..ll"
••
OWTH7
MlATIF'tf-DOSE RfGo'liNS
COIIM'( jlWutly. l'i tllt' r lilt' dllSill ~ inh ·ry"IIlt'l...·ssa ry 10 adJl e\'(- a dt'sin >
lin' Wvt'll at 0, 12, ami 2-t hr. then tlu- concentrunon
o
12
24
36
o
48
24
12
SUIll
36
l)f Iht'
48
Hours
Hours
t' It. 7-9, I>w"'" l""In·"lr..hn", of" ,Inl~ 1:1"''' illlr.." ·"..,,.ly (I.·til ar.. 1m ally (ri!tl,l) "" .. 1i",,1,...... " I" .')41 m~ ..,..I Ii" ..1," "'i,,!/: inl.·.... -..I nf fi hr . nIl' ""'1"·lil",· i. 12 hr. :'\,,1:<' 11 1 tI..· A ( '<: ,Iurinl:" '''Nn~ ill..·....... ;l.1 ,It·;,. ~ ,1..1,· ( 1i~ I" r ..ru.lih ~) i. ... I•....J lel tI..· 1111;;1.1 ·a ,u..lo·r tI,,·(" I",~" ; ,,!/: .. ';"1:1,.•10....• « \.trl .·• .J,...Lnit).nil' t\'1l1u..lit,,, or tI,,· (UK"." lnt lit", i. e1im;"i,I l "1 ,, ~"''' "r..Uy (;l.I ,'1>1 it" . 1....J 1".li f.· i. 1,4 Io rl. 1...1 tI,,· ..",r.. Jo:1· ,"';,.1:•.",..,,· n"""'1,lr..lit,,, i, II..· ... " ll' 11> 1 ..1"1,·r I.•·. ...lmi"i ,l r..lio". ,,·I,,·n. ...' in Il.i' •·...u"I'.. -. F - I. n ..· '''I .",l it" " ,,,... 1 I"ur II... . im" \.tlit,,,S""· l(i " in "I,,,·,..h.. I-I)
t ·IK. 7- 10. T" "·"l)·.f,,,,r . ,,1.)'''1' •.",-h n" .. sin~lt· :zt:l-m~ or.ll ,10....• lIf th. · 1"'11" "
0.5
n .... ·.J
.1;<·,, "f W "'!/: " I" ("'~OOIJ"';"" ll.tiJ:.' (u . 2:! (...." . ....'1;\1· ,~~, n ..· ,>I ..J """""1:" pLaI,..." (·.. ~OOIJ" m ('{"",,·utndit..,
" ..·11 pn..IK1 1
I,,· tI... . -..1, ntk"I" I... 1 1"",,,, 110.. '-inlt!<· ,), . •L.t"."hl;t.i' 1loy .L' i,L"" II..•..H ·C I~' II..· i,,!/: i" I.·....'..! ..",I (·"m..1inJ: f" • •),..... '1 ..· .. ~ ..I Ii,..• i, 1"·rf'''1 pn..l it1if", ( I "'Wi . •."J,1 1l. \l ) (11.,,1...1"'" (n ,,,, <:n..·"I>I" u. l>.J. Ui" ~1. \I .. I'uri. S K.. II... I . i'.i ll ll~'. \I .A . "'KI SI....It·r. H.I; H... I,K....I .i '''I:I. L..••• d.·..nu • .. I" clt~OOIJ"" '" ill ....l..~' nK·" 1' IK1. it"·n· ,,..1 llUlltip..... Ic....
0.4
0.3
.'
t"'·
lIIl'l"U muLatit,,1. e li" . 11...nt""..l.i'><1.• ~; !l.1-ij.j _ 11J'jJ. H., .... h" ....J. " , I" po' n" i"';'II' or .>\ I>IS .>\u. lntLt.. ", ,,,,,. I.i,, " h..i.)
1'"",
o
0.2 0.3 0.4 0.5 Predicted Average Clobazam Plateau Concentration (mgIL)
0.1
.
CHAPTER7
Useful n-lationslnps han ' 1."' ''11 tI,,'ri Wtl fnr d... ~ i)!;n i n,g uml t"\~l l ua lill)!; a dOS;I~t, n-ginu-n ill which tilt" tloS(' ami tin' dus ill)!; int erval au' fixed. Tahlt, i -5 summarizes som ... of Ih... mo rt' important rt ,latinllS h i p~ umltlu-ir lilllit;ltiuns.
CONTROlLlD RHlASE TIlt' mailllt'nalil'(' of it l't"'slt', is "ellit,\-t"tl hy I'tJllslanl-ratt' ittllllilli... tration. \\1Iilt, su mt' I'tJllst'U1I-mh' rdt,it.';t' "i}, tt'ms ha\'!' )I('t'll dt '\1,lol)('t1 (C hap . 6 ), othe-r dusa)!;t' forms exist From which tim)!; r""t'il-'it' is nnn-h slm\"('r than From ullI\·t'ntional tlos.t'r 10 Iirst-onk-r. than to ;/'.l'Il.l-tlnlt,r. Suchcont r olled-release p roduct s donot completely IIhlitt'r.I!t, h' ll d,) n-duo- l't.lllsidt 'mhly theHuctuanon in the plil'ima concentr ation ;tt p lat eau. when l'tllllpall."ti \\i lh conve-ntiuual the-rapy. ami an: pa rticularly useful wln-n maiuteuauce of tllt'r.lj'll.'\It il· n llln'ntr.ltinns is diflk-lIlt or illl't.)Il\l'uit'nt, Til illllsirah' tilt' poll'lIllill vahu- of ('tllltnl lll'll-n ,lt'il'il' products. consider tilt' t'\l'nts at plalt' all simulan-d in Fi!!. i - I I fnllo"'i n)!; oral ad ministration of t1n'uphyllillt·, which has a tlu-rapc-utk- window of 6-20 mw'l. in a elrild with a half-lift, o f 4 hr. With tlw IIsll,,1 dtlSil)!;t' form s, ah'\.tllVtio ll is rapid und, In lTlilinlain ti lt' plaMna l'U111't.'IIIr.llion \\i thi u tilt' Ilwf'dl")('uti t· window, tilt' t lm~ must II(' ad minish 'll.'ll t'\ l 'f)· 6 hr. an inconvenience. ,-\ d m i n is lt'ri ll~ thrcorumlk-d-rcleaw d' lSa!!t' form at IIII' "',1U1t' frt't IIlt'Ii''Y as tilt' conventional fun lllll
,.1,1.7-5•••latl......lp.f.......I...... D. . . . . . . .1••••• EKTUvA.SC\.W
rv
'0'"'
",d" ,
PlATEAU AYE!loge omo.....l
...
...
• ••
•• •
• ••
• ••
•• •
•••
••
•
N
• ••
••
N
No . imum C()I'(: en " ohQl'l
...
Mnimum
conc.:en"Olion
... . ...
,
'J .,. '"'9'"""'"
<J 0'<>UCll doo.o...-d
, ~ ~
~
--..::.i>
"""""'*""appmo~
'""""",, - -
' ~ ,., ~
"'" N.:IV<M
... ~ ~ d o.. ~
, .,.,
.._
1oICM' All.'iQIf'lo-.
·. •• ...
•*"
No'nlenonce dose ActumuloJt,on
"'" » 11 """""'"
" > 1I
II> .
N" N
•••
100
CHAI'TH 7
25
20
f
I I I
I I "~.- --
~
.
- --case A case B
.....
Case C
5
Case 0
o
o
3
6 Hours
9
12
HR. 7-11 . ,\ ,I",i ni, lt-ri ll /.: " limit. lil ,· 11 .".,) l1i"... in" .,onlmll... I·n·l,·",,· ,1<",,1:" f"nn er..I l li"'.,,) "'..~·II"t ""I), ,1o"TI~"'" ti M" " ' K1 11.. lil'" ill 1'1.."", "ot...."I ....til ..' ;1' 1>1 ,·.." ,e · III n""l"'n..lto .ha' , "'tl, tiM" "'11..1 ",¢ITI"n j<:..... .\ ),1",. m..~· "t... I,,-nnit th.- limit to ' '' ' !Quo" fn"I" ,'l~' «:.... 1>), C.....· C . 1"...... tI..•..."......,· Ir.dic,n.litlll' l,n.fil.· ..rkr tI,,· ,,,,,...J do.JiWI.,'t. f" rm (3nl) "'It) 12 hr , In ,I,i••.••""1'"', " .2 - .. hr. \ ' - ;}.') I ~ ,.. - 1,11.. , h..Jf·lif.· lO r rd.~.....· (rnm tI..· n trul..'(!.r..l.·..! I'" "lud ;. J hr. alMI tI..· II,,·r.4l""'I": "i".I.e", 1. 3 In III ,n~ ~ n ..·,.. ~. n,¢ IIIt." . "". Il,O '''It ' fj hr (C ;\ ...., I tU ;1,"1 3fill "'I: ........... 12 I,r (C........ C ...,..1 Il ).
tilt' llsua l rt' w men is convr-utent hut IJol'l.'m lSt· pmlr-dl'Il'l1 rt·le.N· ma y pUI d m ~ into tilt' Inwt' r in!t'slim' o r perhaps out o f Ihe hudy lx-fon- lilt' rl'lt 'll"l.' is compk-te. DI 'l.' n'
Evaluation af a Multlple-Dase Regimen cmd Asseumenl af PharmcKKlnetk Parameters 1111' dl'n ·lop lllt·nl u f dOS
AUC.. .. AUC (single}
24
CHAP1H 1
MJ\TlPlf{)()5lIi'fGl,','.f NS
,.,
is till' ACC withiu a dos illK iute rval at plateau. Equatioll 2-1 is a n'<.~lsli lJK of El l' Zl. \\ liN t· Al l :•• = I: · DI)S(·/eI.. A plateau is takeu to IN.' n'at:llt'd wlwu M...·t·m l t'fIllM'<.·uli\t· t ru u ~h l"llllt"l·lIlmlinlls. dd"nnim't l from bluod samples taken jmt lx-fon- tilt' 1It'\t di N', show l U I tn-nd \\i th tune. TI ll' at't.:ural'," of tilt' esHma!t·s of Al:C.. und ,\ L'C ( s i l l ~lt') an ' Ill';l\ily tI.'pt'm lent on lilt' numlx-r und t i m i ll ~ o f hlood samples . If needed. tilt, ('slima te of ;\ l "C" can ht· imp ru\'etl usin }: st...e ml d(Jsill~ Intervals, which in turn imp n nl-s til" ('stimah' llf C [J F 'II plateau. As Shl)\\ll in Fi}:, j'-~J for dl" J;v~un , C[J F dill'S not d m ll~t· o n multiph- dmin ~ . 1IIIJr-U fe. T his pa rallll'h'r llIay Ill.' d ilTit'u lt to cstnnute t1ll ri ll~ multiple dos i n~. Ct.·rtainly, half-lif(' canuot l«- ('sti lllah"ti wi thin il dosi ll~ iute rv a l with all)" 1"l 1ll ~ t1(·1I1't· when th e dm iJl~ int e-rv al is short er t"
wln-n- AC C"
Obwved occumulo tion
25
inde x
wlll'n' .-\ ['C ( I. t ) is lilt, an 'a IlIJIII'r Ill(' pJ.l\ l1lll l"lJIlt"l·IIIr.llioll-liIlW profil(· c1 n ri n~ IIII' first t11 ",in~ lntl'n 'al lo hll ll' t . l 1w pn ll."I"tlnn.·. anal{)j.~ons 10 IIII' Ust· of " ... vlllul'S ( Ell, IOJ, is iIIm lrah"ll ill FiK , -1 2. Oh\i nn sl)'. a pn't li(1inn h,L\("t1 nn till' m l i n AUC ( sin~le )l~\VC(l. t ) \\ill lilait'll lilt' uhst'I"\'l"l1 mhu if ,'\ L'C" = ,\ L'C (silll.:lt· du.se). TIl(' I.l\llt'nn is tlat" total ..\ L'G afkr a s i n~lt' dll\('. Tilt' vailI\' t1t'lI'rminl "ll by El l. 2.5 i.s llppru'lilll
CHAPTfI1 7
102
f111l'tna!ioll is tilt' m!io (C - C m)/C..,,,•. An ad\'all la~t' o f this uu-as un- is that it IIt'als wit h C u... which art' thl)lI~hl In havt' n-h-vunce with rt·~ I)(·(.'1 10 l't , m· lalt~ of sa fetv and mtntmum (' lTil'l ll"\', :\ d isml\1U1l aV;t· of th is IIlt ',t'lirt' , 110\\'('\'(' 1". is that it rcln-s nn only' roll ObSl.·l"\~ollillns. t lllt' 'o f which (,'...""". ) is oftt-n difTil111t In tosti malt' i11't.·lIntlely. unless mOillY hlood s amples art' taken wtth!n till' dosin ~ interval. a n ·lati\'l·ly uuconunon cliuiea 1 pract ice . Anotlu-r 1I1Oft· stahh- nu-asure of Huctuatktu, wilieh is k-ss dept·ndl·nl Oil si ll~lt' observmous. is ~n'lI by
26
wlw n ' ,\Ue (al)()\'(, C........ ) aud AVe (belo w C...... ) arr- till' ,m',lSabu\"(' am l l"-' ]el""tilt" awmV;t' concent ration at plan-au (A VC•.'t), n.·spe<.1iwly. Est hnat iou or tllt'sl' values is SIlO\\11 in I!\(' inset I" Fi~. i -1 2. Other Parameters. Equunon 2i forms a usefu l I l;L~is t11'Il' nllillill ~ rt·lali\'l· bina\'ailah ilil)' or it t1m~ adll1in isl t'rt't:l t-Xlnl\1L\I:ularl)' ( t·.~ .• u r.tll)'l. bcotWt"t'1l t\'" treat nu-uts ( t" ~" dnsa~t' form s A and H), l f dea ra lll'C' n-maius llIl('hall~I ,(1. tlu-u
rur
Relative b ioova ilobility
IAUC..Js IDose)....
27
IAUC.,}• . IDo..I, AUC (above c....)
"
50 40
~ g c
o
30
5'
~13
2
4
6
8
Time In Dosing Interval (Hours)
20
c 0
'-'
AUC(I . t)
- -__<:: AUC(single) --- ---
10 0 0
24
48
AUC" 96
72
120
144
168
Hours tl,lt. 7_ 12. E\~Mti.." u( a II1 Ull l"" ....Io"'· " ,Qn,,'1' , 11,.. \I .. hihl~' of till' CU r rdlio "ith llo" i""('lJ,I..•..\.. 'S .... I I~Ih. · m .. t1llrinK .. <1o,.jnK i ntc·l'\~ ..I p1atf''''' (A t·C..) I.. that ..I' till' tol,.] ..n· fit·, a 0111"'" , 10...• (Al'C(oiu0t- »). n..· ,~ ... of *,~,"mlation il la kf'Il"" II..• nolioof' Al'e .. 10 II..• an 'a t1"n"KtI li"t ,1o,.,j"Klnlt·I'\"..J to IiIlM' t (ACC!1. t »), ".,.. I.alf-lift. io h,'S! ,Io-l..n"irM ~1 a(h'r ' '''I'pi"To: ,In' f( a11", lnl\lr.lic>ll , n..· in...-I .1" ,"" II..• ""-11,,,,1 f"r ...tim"lin" tI... d.'W'... "f 0'" 1n"'I" " 1.........1 ,>I, Al'e: (E' I_2fj ) .. I"......,..II,,·",", II..• ..... r.f(.· (~Il K~ 1.tr. · tWItI. C..... " it IIi" I...• <1o"'lllK illh·",'alllf p1al.·..u. " Il<'n...li ....~-. it ('lJ' h(· (~..llall..1 frum II... ' .t""·r....llIwU mu m llIMI minim" m ~~"M~·llt nolic".s "I pLol.·.." . C ..,_. C..,_: (10,.,....· ..( 0,"1,wt i.." - (C .. ,_ , - C..._J/{ :..,_, (~ltllp;uinll:
10>
CHJ\PTEIl 7
Ih 'ual dt'i\r.UH.>t' t-au lit, t'sl illlilh-<1 from tilt' amount o f dnt~ excreted unchanged in a tilt' \"aillt, o f A UC ...
l lusi lJ~ Interval al stt'ad~' sta lt' , AI'.... and
28
l1:enol clearance =
The rt'la m '(' h iua \'aibh ility o f ,lII extravascular dos(' lI\ay lit, dl't/.'n nint'(l from uri ne, us \\'(,11
,t" phSlll
(Ae....)B (Dose)"
..1.. . . (Dose)s
(Ae..
29 STUDY PROBLEMS
(Answers 10 Study Problems ore in Appendix II .) I. Ct lllllllt'nt »n tilt' , U.'( ' lI l'oIl 'Y of tilt' a n ural multiplt'-doSt, « 'I.'; IIIt'II.
follU\\in~ statements " i tll n~lrt l to d nt gs gin'lJ i L'
a. :\('('lIl1l ula tinn '11"1I~~ IK,('UI'S. II. l1U' t'xlt'u l of ,t('( 'ulIllllatioll increases whe n drug is giW Il It~s fn'llut'llll y. c. 111(' ti nu- III n-ach plat('au follouill g: a multiple-dose ll'gi IllI'1l dl,pt.'nd s O il tht' In " l lll('''t~· u f dmg adm inistration. d . ,-\1 plalt 'all. the amoun t Ilf dm g: lost within a t10silJR interval equals the oral main It'n au ('(' deISt', I'. T Ill' la rgt'r' rlu- \UIUIlII' of dis tribution. tlu- low(' r is tilt' a\'('rag:(' plat (""1t'UIl('t'ulmtielll. f. 111t' il\l-mgt' plateau coucentratum depends on the ahsCJ rp tion kint1it's of till' d nt g: fol1O\\i ng admin islration of a r~n1t'1l o f a fixed dail)' tlc)S{', 2. ( ;aITnt'r'I'1 al. (G alTm'r, G . JO!IIlS.S0 1l. G ., am i SjOj,.tn'II, . J.: Pharmacoktncncs o f procdnam idt· intm \l'Il11mly alltl n mlly as t1mn'ntional and slow- Il'lt,,'-\t' tablets. CUll , Pharnmml. Ther.. 17':414-12.1, 1975 ) compared a rapid-re-lease wi th a ('(mtmU(,,!-rt·IC'l:' tablet an d I g ('wI)' S hr us tilt' cout mllc '(1- rt'll';(w fonnu 1<11ilm.
AUCIO.81
.....IU
226
Ropd-relea1oe lormuloll()rl Conlfolled-releo!oe formulol,on
211
a , Cakulan- till' n 'bth '(' hio
V -280l Cl - 4 .5
l/hr
.04
CHAPTEi 7
a. Givl' n Ihat abso rpuon is instantaneous n-lative 10 eluuinarion. calculan-tlu- f{lll ( l\\i ll~ wilt·" a 50-inK dust" of d .lnrt lmlido llt' is taken da ily at breakfast. I. TIlt' maximum and minimum amounts of d nl ~ in the- hody at platt'illl 2. TIl(' accumulation ratio 3. Th e mini mum plasma couceutration al pl att'lUl 4. The timt' reqoired to 'ie h il"\'t' 50% of pbtt·au h. Complete- the tablebelow for tilt' t10S
,
,
c . Pn -pa n- a sketch Oil ~ llar grap h p;.tlx· r of tilt' amount of {'hlo rthalidollt, ill tlubod y \\illl ttmc. Show the salient fea tu res of il( 'l't lll lll lat itm of this dnl ~ dll ri n~ tht·mpy. d . If requi red. wha t is t1 lt·lu.l(lill~ dust· of dilurt halitltllll' II(·('{I('
tilt, ('tllldi tioll at plah'pulmonary di ~ "lst '. is to lJt>start ed on an oral regnncn o f alllinopt.ylliJw (&")<J, of whlch is tllt"(lphyllilw), 111t' plmm llK''f)kim'!ies 1ls fo r a typicoll pal it'lit popnluttou with this ,Iist'jl'w an.' :
F
II:
1.0 (lor theophylline}
V . O.5l/kg CL .. 4 0 rnl/hr/ lr.g l)esiWI WI ora l dosa~,> rt~lIIt'li o f fllllirwl, /.yllilw ( 100 - ami 20n-llI~ tablets an ' marketed) for this p atien t to attal' l ami maintain a p ia-u na cono-m ranou ....i thi n rln- tlu-rap -uuc window , W to 20 mW"l.. TIll' absmVliull of tl ll'oph~·lt illl' is complete- and rapid . 5 . T alll.· 7-7 Iisls a l)pkal plas ma concent r ation- time p m file ohtailll,(! f()llu.... in ~ an oral 500- 11I~ doS(' of a d nl ~. 11l(-' A l 'e is f)U.fi m ~- t.r/L. and tln- h 'n llinal half-life is 5 hr.
Time [Iv]
o o
23
2
4
8
12
47
52
40
28
06
36
48
01 4
0.0 3
a. \ \ 'hat o ral dosi n~ mit' of dnl~ is 111"("(1''1.1to maintain all a\'t' m~e plate-uucoueeutration o f 10 m/ifl. ? h. The decision has 111.'1'11 m .ll lt>l o ~ \'(> till' d nl ~ Hnl'l' ('wry 12 1Ir. \ \ 11011 is: I. 111l' unit doS(>s t Tt" n~ h o f product IWt"(I."(I? 2. TIIC p lah" lllt rou~h concentrunon t':o: pt"l1t'l l? 6 . Tl u- tlwmpt,t1til' do",,>o f a mpid ly (compared to ,·limilla tioll ) aud (,(llllplt·tdy ab sorb, '!1 d rug is 50 1Il~. A conrndled-n-k-aw dUSlI~t> fon n 10 h(" ¢\'I'll ('\"('1')-' f) hr is t!esiWlt'!! to rt ·I. >il its con tents I 'H " l / y and cmll/lff'fIo/y (nn IOiUli ll ~ dose) over IIIis dos ill ~ inh-rvul. Giwn that the half Iif.. o f til(' drug is 4 hr : a. H ow much d m ~ should the ('()lIt m llt'(l- rt>!t'aw d()SiI~t · form l,(lIllain?
..
,
h. To ;I("l.it"\l' a p rnlllpI I' ITt't1 . a rap idly ab sorh..t1 dOS
2? d. In tubular form or
1111
tilt' ...U1U'
~r.lp h .
pn l\id(· till' rl'lativ(· amount s of d nl ~ i ll tln-
hntly vr-rsus tilllt' ('IIT\t'S l'Xpt'<.1 t'1l wln-n till' (.'u nl rnll l't !-n ·]t·.L'it· pn'pamt ioll o llly is ¢H'T1 (iJ ('\l' ry -I hr (ii) ('w l)"!'i hr (i ii) en' l)" 12 hr. ' . Adinai'nbm is it t1nl~ nmh-r iliwstij!;at ioll for the treatment o f depn-ssion ;tllli pan k disun lt·n. Tahle 7--S summarizes v um- nftllt' salient p lmr m 'll'o kilw l i<.· info n na tinll flllICl\\ill j.( sillj!;lt' a nt! 1l11lltiplt· d OSt' s o f immt"tliah··n,lt>a.<;t· and (,(lIIlmll('(!. rt'lt 'iLs(· product s.
'."'.7-8. M_" A..I_••I M.ltlpl. D._." ' .......I Orevp .. Ivltlech-
'6
PIMI
_ ••I....c ..........._ ••I _.IIMII e-trelletl•• • I__
AUC Img-tn/ll C"",. lmg/ U T""," (t,,)
o 57b
1.72<
0 15
020
Te<m; rqll> / l (hrl
220
1 00
... <J'
J.UC 1O-14i _
IIHI .
1,57< 0 11
088 b 007 250 550
f .......... . . JC O"\d W'<jo C E ~.,."'"""."..;~~_d 04"""'*"" ......,.,..>:Jt>l,;.,.~"'"'...;"p&o.o-~ ~~.. 9 . ~ 7- 0t61 . 1991 'AUCIO-, d
II ,.INtIe
_O"\d .......
<J._
'do¥
a. \\110\1 mh '-limits III(' t1(·(:lillt' of pJ.~\lIla atlina/Jllam coucent r anon fnllouin ~ IIIl' administration nf lilt" controlled-release p m(llId? h. 011 multiple do~ill~, han ' tjn- illllll("(lialt·· rt'1(·iL\(' am l l'Ulllmll("(!· n,ll'a.w products 11("('11 ¢n'lI I(JII ~ (· nnll~1. In ('J1~lI n' that II plate-au sho uld have lx-en n 'ut'hl"(l? In ytJur an swer, indi (~lh' wlwllll'r iUl~' diffen-uce is eXpt'(1("(1 in lilt' tinlt' In n-ach plateau 11('lw('('1I Ilw " \ 11 product s. c. For both p n ll!lll1s, an' ti l(' p1' of adill:t7.nlalll of III(' {'tllilmlll't!-n·!(·a....• IJrll(Illl1 ('()lIlpa n1 1In till' illllllt·diah'·n,ll';l'i(· pnl(lll{1? e. {\ n ' IIIl' phart lla('()].';m1ks of udiuaz olam afh-r udmiut stranon flf til(' Iuunedlate-reIt'iL\p alll! tlu- (ulltmllt1 !-n,lt'il'i(' products such that tilt' terminal half-lirt' m il II(' tll'lt 'rtnillt"(l \~i l i l i ll the- n ',,(x"(1i\'t' t1u"ill~ Inte rvals at plateau ? f. \\1...1 are tln- d( '~I't "('s o f accumulation a\StM :iaft"(l wtth the illllll("(!i;lt('-fl,It"l..'it' anti lilt' coutrolh-d-n-lease n'WlIlen~ ~h l' n tlml IIJ(' AVC(O 10 N IIr ) and AVG(O to 12 1.1') f"llu\~ill ~ tl.t' ~ i ll~II' 40-m~ imm(1Ii;If('-n·ll·a..'it' product and Ihe fiO-m R conrrolledn,II'a\(' pnM!lll1S an - II,-l.') and U,-l.J mg-hr/ l.. n'Slx"(1i\'d>'? Ba.'it., >'tIur calculations 011 ..\ l"G (~IIl~ i dt'm tinn~ ,
I
Se c t i o n III
PHYSIOLOGIC CO NC EPTS AND KINETICS
MOVEMENT THROUGH MEMBRANES
OBJlCTlV£S The Ieode!' will be able to: 1. Define PJuive and focililoted diffusion. octoe tronsport. 000 permeability_ 2 . Di!>l;ngui!J, between perfusoon role-limited and permeability rote-limited passage 01 drugs through rrembecres.
3. Descnbe the role of pH in the movement of drug *lfough membrOr"l8$. the cceseqceoces cl the levefsible IlOture 01 ~l 01 drug$ through men't
4 Describe bra~,
So far ill tl.t· honk. emphests has lx-en placed 01\ k jud i<:{...-en ts follu"; I1~ dn l~ itd m i ll i s l r.l~ fion ami applica tion of pluu-macokuu-t ic princi ples to tilt' d t·siJ.,lJI and e...-aluatiou of dC lSa~(' n.';Illt'IlS. Littl e has ht't'll s:u;n ~ physinl f ~l'lm ll"t"Ss('s control phar1Il00(:o kilwti c pam uwt Ns . }l ·t such infonnaliol\ p n l\;dt"S an illSi ~ht into the intern-latinnship s lx-tween d m g and bod y. It alsn la)'5 a fOl!mLltioli for ilJ(li\id ua Ii7..at ton o f dnll?: themp)", tlnsllhj('(:t of th e nex t sect ion. Thls section explo res till' physiolo,,; c l"Olll't' ptS I l
chapter.
TRANSPORT PROC£SS£S Cellular mr-rnh ranes ap p('a r 10 be l'tIIllIXISt'l1 of an tnm-r. predominantly lipoklal, mat rix covered Oil r-ach surface by d t!ll'r a routtnuous lay('Tor a latt ice ....o rk of p rot ein ( Fig . S- l , up pe Tsecnon of d l"d",ing ), TI lt' hyd rop hobic portlons of IIIl' lipid molecules li n' nrte nn-d tow a rd tlie center of th e me mb ra ne and lilt' outer hytl rnp llilie n.~ollS fare tlit, slIrrnu lI(!ing aCJIIt'()1lS envi ron ment. Xarrow a{lllt'olls-fillt'tl channels exist be-tween some t't' lis ;1-" ill lll piIIary membranes a nd intestinal epitlJl'Iia . TIlt' I rdn~lx l rt o f t1n1 ~S is n ftt'n viewed as 1II0\'('lI\t'lIl u<:nlSs a wrie-s o f membranes uud SP;K"t·§ wh ich , in UAArt-gutt', 5( '1"\'( ' a.~ It "funct tonal" lIlat'mst~)pi t, nwm bra ue . TIlt' ('t·lls ami interstitiul SP;lt't' S rhat lit' ht·l\o."(,('!1 Ihe ~;L'lril' lumen and the ca ptlla ry hlood and rlu- struc-
...
110
CHAiTH 8
tUIl'S 1)('1'\\'('('11 the sinusoidal spal" and the hill' canaliculi in tilt" liver, ,tS well ,lS till' skin (F iR. 8-1), art' examples. K.lch of till' i ll h''1)usi ll ~ cellular nn-mhruues and spal"" illll)('(II' dnl ~ transport 10 'll.I)ill~ dl'g n-cs. ami allYone uf them can rate-limit the o\"l'mll pIlK'{'SS, In the skin, the stra tu m cor neum is till' major ..itt' of impt'(!a lll't·. It is th is (·'Ulllp lt·li.it)' of struct ure that malws quanntatlve extrapolat ion of d m ~ Iruusport (mill O Il(> IlIt 'mlmlllt · I II anot her d ifficult . A des<:riplin n o f the qualltatlve feutun-s of lilt' pm(" s<;t's of lim).': tra nsport ac ross t ht·S(' "Iuuct ional " membranes follows .
Diffusion and (onvectio. ~ I ()!it t1m gs pa.ss thmugh un-mhranes by tliffll.vloll. tilt' natu ral !l'mlt'lIlT for molecuh-s 10 1lI1l\" dO\\1. a concentrurkm gmd it·nl. ~ l l '\"l' lIl t 'll t n-sults from til(' kint'l k ('Jlt'~. (If II\(" molecules.
Cell membrane
- - - - - - - Hair shaft Stratum
Epidermis
corneum {
Sweat gland duet Hair follicle - - Papillarylayer - - Tactilecorpuscle ~ - cap illa ry
lIf:7f-::::::::I=:::::-= Sebaceous gland ". - Nerve
Dermis
- -f-- - - - - - Arreetor pili muscle
Subcutaneouslayer Fill:. H- l. FllIll.1 iun.l n..-ml,roll""1 '· in ,1" ..1" .. ' anc! tlud" 11..,y (":II.n I..· a., ,hiu ", .. . inlt"'" <Til ....·mb of appnm malt·!:o· J X 10- 6 ('m Ihil..knc"SS (1,'1 ' ). Ill ..... ,hil..k 11.' I · ll1Ulhn -lI"L.rh..rrit·r of II..• . kiu. TI,i. lll" hic. UuLu loaTTit-r n l"11t1s frum tI... ll; a ,Iht "l" " · ,.( "1'I,m~ ",al" I:o' :2 x 10 - I csn (I. lt l " m). TI..· ( 11 nlt'", l>nult' ro rnl,ri..." 1I 11i1"'.oI."("ULu lo,aI!('t. "ilh 1I lipitl inlt'rinr ;
1tIo.l:..,w l
ri n•. tlo'J'k1....I... ~ .. ..it.I im 'J1;lllar .J"'I
I I""Ii....((;,.11 mt·"' lmUlt- "l'""llI.......1f" "ll Sinl:l·r . S.J. C:.I&: TIlt' Auiel ""....k " "Kk·1 uf I 11, ...1111'1' "I' (.· 11 IIJt'mhnm... , SCl f.SCf:, 1; 5;720, 197:t " 'P:'"'I'i¢'1 II}'l:2 to,.. 11K- A1\A S; . kin ....... kiIK~' drawn by \ 1;4"'!>' ~ "rt ld "", I S ir.
CHAf'IH
a
'"
T n app rt'(;alt' lilt' pm p..'rtil"s of p.tssi\"l' d ifTnsi..m l~ JIIs itll'r a »ruplc- s) 'SIl"1ll ill w!lidl a IIlt'l1Ihra rw 'W 'llarall's I\..u \tl,lI·stim'll ,UIUl'lIIlS l'(lmpartmeuts, TIlt' tlrh ing force for d m g tran sli'r is Ihl' ("Illwt'nlra!ioll of tilt' d j fTu si ll ~ Spt't.; ..... in t'adl of tilt' e unp urt ments on t'itlw r sitlt' of tilt' mt'lllhr'lllW. TIll' li d r an- of penetr ati on is
P
Nel rete o f penetration .,
Permea bility
SA Scrfoce c rec
. lC..o. 1
C..o.21
-
Conc entrati on di fference
111t' im portan('(' of lIlt' surface urs-a of til(' membrane is n 'lillily ap(litrl.'n l. For example. tltluhli ll ~ lilt , Slln. lt't· an'a dou hlt... III(' pro hahi lil)' of collision with tilt' membran e and tllt 'n '''y ill('n 'aw s tl.... !It'nd rollioll rah ' hmfold . Soun- dmgs n ·at lily (lilSS I hnm~h a uu-mbram-, others tin lint. 111is tHfft'n'n('(' in t·,('\.p of Ilt'lIt1roltio ll is flullntital i\'t'!y ..-xprt-sv -d ill !t' f11I S of 11..., }wnlll'fJbility. ~ o!t· th at lilt' p roduct r · SA has till' un its I)"pil~.ll of How. I't'nnt'ahilil)' then-fon- has unu s of , '(,Jot..nty, distance/time. T Ilt' tlm't' lIlajur ....lIln '(·s of variatiuu ill pt 'nllt'ilbilil>' of a "'';\1·u lIlt'm hr.ult' 10 a drug an' lI1ol"'('nlar sin', lipo pllilid ly, anti d largt'. \Iolt'('ular size has lilt1t' imp'1l1 till d ifTusion of stlhstalln 's in '\111t'r h UI l ias a majo r d T..'<.1 n il 1II0\ "t'II lt'nt Ihn MIRI. IIlt·lI1h r.lIlt'S. 111is is pn 's ulll ahl~' n, lall'l l tn lilt· struct ure of membram-s. For SO IlW membranes . wah·r ·solublt· materials mu\'(' pamt"l'lIularly tI ln m~11 narrow channels Ilt,ht't't'!l cells . Hen- ilgOlin, moh-oular ~ i7.t' is important. ,l~ an' shapt' and dmrgt' of tln- lIlolt'('\II,' . For t'Xilmplt" oxytocin, a (.,.,·Iit- 1Il0lIUllt'plitit', paml'(· lIl1lar ly (·ms........ tilt' n 'lati\"t'ly looSt·ly I.....n it nasa.l lIK'mhr.lllt'Sfluitt· rapidly hilt is almost totally IIna"I.., 10 cross tln- more IiRhtly kn it g'oLstmi nlt'st hml IIIt'lIl' brutu-s. \ IO"'lIlt'lIt of \\1111' r thn mgh tilt' pa racellulur channels (a ('(JIl\t'(1h1.' p r ocess) aids in li lt' trallSport of suhs lall('('s hy th is rout e. The second sonrre o f variation, lillt'philid ly. is ofh 'n d l
Molecular Weight (Olmolej
' 00
-3 -4
L
-s
,,~
-6
~!
-7
c,
-8
u~
E•
200
"" 600
800
-, - 10
"----4--~-~
o
:2
..
6
OctanoVNalerParlrtiOO Coetllcient (log sea!!)
t·l ~.
H-2.
r..· m ll·....hihr;.....·.. M
...... r"'....i i" o
~li tl
of " 1I.......~J Lo.r \i n> IUMI
hl"'l'hihdt,., LiI"'l'h ll ll: ity i. /'\ 1' 1 .... , Ill' '1I'f;lnnl/wa " 'r f"' r1i. tkMI ·ffit...·n l. E....... lilJt' " 'P""""nb ."I lll tll:"· S o r Ihl' Sin n/, " ", I<"('1 ,lllr .....Ilth! b" l t1 ilT..... nr hIM'I'I,lhd t,.. ( ~I ,.li fM ...1rnm' Puth , "0, "'MI Guy. " II .: r ..~ Ii<'finK .lm I"·rmo...loilily. rt rm. H,.. .. 9:ffi~. lW-l. " ,.. I' I"•....Iwi lh ['I'" " i..io" or PL'nllm 1'1.I'.li"'i,'II: ( :.....p' ...." '.. ", .)
112
OWTEI!8
Thus. t he la~N an d mon- po lar a moh-cule, til(" slowI'r is its ~lt)\l' Il1 I' nl is
slowr-d , '\"l'1I m ort' if , hI'
lIlUH'lllt ' ul
11I011'(.'1.11(· is 1·lIa~I'(I .
AuolhN determinant o f jlenJwahilily is memhram- thlckm-ss.
tilt" di slalll't'
it
1IIoll'('ult'
IllL" to Ird\"("J'W from t ill" sill" o f int t' n 'st «-. ~.• a n absorpuon SUrfl' S o n hoth skh-s ll( till' membmne. ~I O'''(' III{'ll t of dmg IIt,twI'1-'1\ n-W0 lIs still continues a t I" \lllllll W S of tilt' ll:J1 l1 pa rt lllt' lIts , to and From wlJidl til(' dm~ is transported. a n' small. Initiall)', when all tln- dnl ~ is placed Oil Ollt' sid t, of tilt' lIlt'lllbr.lllt' , it fnllllws from Ell . I that ra te o f dm~ transport is t1in'(:tl~" pmportionul to ronce-ntrut km (Fi~, ~ ) , Fur I' Xample , rat e o f t r.lIISpo rt is i lll'rt"L~'(Il\\,lfold when conccnr rancu of dm~ is dlluhlt'll. Sta h'!.! difTt'n'utly, each lllolt'{'u !t' dHTuS('S iudl 'lx ' udelll l)"o f th e otl u-r. and tilt' sph 'lII c umot lit, s aturated. Unk-es a dm~ a ltl'rs tlw nature (If tilt' mc-mhrau e, tilt' last stat euu-ut a l ~ l a ppls-s wln-n th e uther lIlo lt'{'ul(· is a diff(' fl'nt dOl~. Both ahS('II('t., of l'l llll!X'li tio n III'tW('t'lI 11I01· t'1-'lIl('S alit ! Iaok of soll uml io n a n ' t'ha r.lt:I('risl il'S of p;L\ sin ' di ffus io ll.
Carrier·Med"lCIIod T....porI ~It' lll l mul('s are 1101 inert barm-rs: lilt .,.. han ' a s!x'!.'iali/.('(! function. ~It'lIIhr.lllt's maint ain l'ld \l{ li ll~ or n 'llIo\"iuj,t sonn- mat e rials and 'it"lIIlI'SIN illJ!; Of st'lt"i.1:in'!y n'l ai ll ill ~ \i la l substances. ~I any of tilt'S(' compounds a n ' po la r, ....-ith low lip id sn luh ili!)" )'t'l Illl'y pene-t rate membranes IlUll.·" f:l\h' r than anl i{·ip' llt'l l fnr fl
the- Internalcellular environment hy
II ~S ,
TIlt' l.'1 ll1('t.·pt of a carrier stems from tln- observation of a ltnnn-d mtl' of t ran sport a t inl'rt'nl \\i tl.o lll t'!Ilpt'llll ih m ' of ('Ill'fK\·, a nd a t ("(Illilib rilllll. tht' {'1 )l\('('llt ml io lls in ami surmtl lJ( li ll~ Iht' n 'll hlolltl ('I'lls an ' t"lpml. Al hiRh pl.mllil Rlul'l)s(' ('1 J1ll.'(' ntml iolls, IIt1'\\"(,\'('f, tht' mit' of t nlll sport of ~1ll('11st,
n,;, /01-3. I nil W M " u{.In'l: Ir""'l'urt P 1'~ Jl "'t 1 It(.li''.1 tiM' .~ >rM~,,,t r,,liun n{ tlnll': I>I...~ ..I un ,,,...
Passive Diffusion
til .. n .. ·mh........·. With P'-" r.•. ,lifT",itl", tI..· ...,,1., of 11'lU"1">t1 itlO."",""", h,..·lt1!:-· ..ilh IO.... nI r"liun . Will, (...rrio·r .n Ii.th~ l lr""'l'un . tI r.lt' ,,( Irall' I" >t1 ..Pl'.."" ~ II 1illlitjn~ ,,.J, I l,ilQ' \lt ~.
" >"t~'''t ralic>" •.
limiting Rate Carrier-Mediated Transpon Concentration
Il3
into tlu- ('1')1I1nll.')11· TPill, l. t· " a limiti lll!: value or tmnsport maxinnnn. Furthermore, ill commOll wit h otln-r (. lr rit·r-ml'i.liah 't! S)'SIt'IIIS, ~I II(.·()S(· !rdmport is n-asonably sj>t'(:i fle ami is inlrilutccl "~' ulliN slIll!olrah·s. FI"WdmJ;ts IlIl
is tln- transport o f vitamin B12 ilt'ruSS tln- ~a'il rui ll lt'st i ll:u t"pi111t'Iium . E\il mpll's (If (J(1in' t n"'-~IH 'r1 ahound am i ind ude renal ami hili,u) ' seen- non of IIlllll~' adds ami !JoN 'S. see n-non o f certain ad tls 0 111 of til(" central 1ll'I'\ U lIS svs tem . and int estinal absorption of sonu- amino..~·Iat1alll ant ibiotics and all wo!t'l\sin -<"'()!l\'{:rtin l!: e nzy me illh ihi · Io n; via tln- dipt·p tit lt· trun...po rt sySh' lll. C llamt1t'ristks in eonuuon wit h p,l-'ish'(' fad lital('(1 di rrll ~illn an' ~I t llr.thilir:o·. ~p(·(..ifk it>', and competitive iuhihition. Acnw trallSlx lrt is d ist ill !-rlli~ llt'( l From p'l-\ ~i w f"d lil" h'( l d i fTlI~ illn hy th e Iwt movemen t of su bs ta u(:t· a~ai llsl a u lIIu: n t ra tio ll !-'T;ul it'lIt, which ran he la~t·. 11 1t· maintenance of tllis Wadit"lIt requires mt't aho lit' t·l\t·rl{v. At1iVt >tran sport m il tl lt'n ' fo n ' be impeded hy lIlt"tahol it' inh ih itu r'i.
BLOOD flOW Blond . pt · rfllS i n~ tissllt·s, dr-llvr-rs a lld n'llIon's substa nces. At'{'(mli ngly, 'it""i ng any tissu e :l\ a wholr-, t ilt' ml "" ll\t'lIt o f d Ol)!; t1lOm.e;h nu-mbram-s cauuot II(' divorced fr om fIt·rfu sioll t' J1l~ide ralinll\ . I't'rfllSio ll is usually expressed in un its o f m l /m in IX' r \1llt lllW (o r Jl\olSS) o f lissut·. \ \ 11('11 Illt' l1I hnlll tOS o fTt>r \irtually no barner. tilt' slowtost o r ral c.limit in)!; sk p is IX·rfllSio ll, 1101 IX"Olll'ah ilily. a.. .. sllO\\1l ill Fi.e;. k--t . This pt·rfusiou limitat ion is exemplified ill F ig. 8-.') for t ilt' !lil\S;I.e;e u f certain sub stances across th e jcj unal nu-mlmmes o f a mi . From lu me n to hlood . T ritiated water mo... es fn >t·ly thn m.e;h ti lt· 1IIt'III Im lllt', a nd its rate- o f pas~.e;l' Increases \\i lh illt·n ·.l\ill .e; perfusion. Thr- p
nit'
A. Perfusion-RateLimitation
(
~~~- - - - - - - - - - - ~ ) Tissue
B. Permeability-Rate Limitation Blood
Tissue
Fi lt . 11-4, n...limililllt .t, l' mnlmlh,,): r..l.. IIf II.....••
""'III of .In l!' "'-.......... II...mhr-oll..•• (n)fl' hI....I h. h..,..• .... tI..· 0'(1""""". ,ouio:"..". If II..• ''It''mhr-,uM' (llTt'n T..' 'Mh l........, tim): in II..• 1>1<..1 It.,,' in lt 11M' Ii i. ilt virtu..! nl"ilil.rium .,.ill> 1h..1 ";lloin h ·; hlt l aI..1 IT"'''' nl~' t....~ a.' U'It'. 11m ' " m...'1 of ,In llt i.Ii"'i1...II~· 1.",,_1 R< n, .'l l nn I>.h~· .r"' .. lirnil... h tl" if n.. ·"' I> n...i " ' · Itl tlml{ ·" .. ..,1 I....", .... ~ hil(h; ,"' ·lnt·"1 tw· i. 1..",10 .It...· 11""..,• •iIi,.· I" (-h.."I:''' ill ....rfll.it 'lI" I, ' ..-pli],hriurn " ,,,'" ;l( -h ;"....... I I~· tI... tin'" II... hlt..II. ·..... .. II... ti ..,...; "10..1 al..1 h' " w ",,,.l 1M"""' I,.. , it.......1.., " ,,,,r.. l.. ('''''I'''rl· !l..·"h .
M:I".
"'
III()VE MENT fHI1QUGH MfoYBiANES
orhe r larger polar com pounds than for ethanol or water, whkh results ill illS('ns ili\; ly to changes in pe rfusion (Flg. 8- S).
Some co mpounds. likt· urea. have inte-rmediate pt'mlt'ahility charactensncs aenl'is tilt' jt'jllllll lll . At low h l(XM! flow mit's. till' compound h a~ su lli dt'1I1 time 10 Ir.l H '!"St.' tln-
membrane so that pe rfusion lx-comes ml e. lill1i li n~. At h i ~hl'r hlunt! flow rate-s. !ltl\\1" "er. membrane 1N.·om·ahility !JI.'<.'fllllt 'S lilt" !"llll o. lim iting step. an d abs(J'l.Jtioli 1"'''('(lIIlt'S rdilliw l~' luwnsttlve 10 blood IInw (lo"i ~. S-S).
IONIZATION Most d m gs are weak adds o r ....'·ak bases and exist in solunou as an r-quilihruun hdwt 't'li lln-iou i7.l't! and Ionlzed forms . lncn-ased aeeutuulatkm o f d m g uri till' sk!..• of a Illt'lillmu l(' when- p H fa\'Ors greate r i(Jll i7~lti nll o f d m~ !IlLS led to the I' ll parlltul/i 11I.I1H It1lt,.~ i.~ . AcL''Un l i ll~ to thi s hypothesis. only un-kmized uoupolar dru ~ pe-net rates till' lIl('mlmuw. and a t eqnilihrtum , the concen trat ions of til(" un-Ionized species are equal Oil both sitlt's. TIle majo rity of evi dence s llppo rt i ll ~ tlu - p I! p artition h)lx)t1l1'sb slt'IllS From stud ies of gd-st nl intl's ti nal ebso rp non, renal exerenon, and ~iLst riC se-cret ion of d n l ~s . The- 1"11 o f g.L\tril: fluid varies lx-rween 1..'5 an d i .O; urine pI! fluctuat es I)(,tw('('u .1..'5 a nd i .5. El ~'wht'f(' ill lin.' body, chan ges in I'll ten d 10 he much smaller and to show h-ss dt', i atio ll Frmu tln- 1"11 of blood. i A . TIlt' un -ionized fonn is assumed to 1)(' s u ffi<:i('1Jt l~' l i pop'l i lil' to traverse membmm-s. If it is not , th('()!)' predicts tha t tln-n- is fl O rrans fi-r. irn'slx'l1iw of p ll . 111(' fmdioll UIliOIl;:t. ed is ('(IntO/I1('l1by IXlih the I' l l and tht.' 1'M of the d m ~ al'(-,ort li n~ to Iht' II('udt' rsonHa....sd lmlch equation. T hlls. fo r acids , K
( Ioni zed concentration )
20
pH '"' p a + Iog, o UrHOtIized concenlrolion and fo r I"L'it'S
.11t. I!l--S. TIM' ""•• of I"'L~' "I' a .ul"la'...• ...·m... II... jo'junllm of .. n ! ",-a,. ' ..'1'·m 'i..... II~· nM'II."lrin~ ih r..tr " I' apP'·lIl'll.llff" i" int,-sli".,] \ TT 'OUS ' .....1. n il' P""""Il'"" bIo:..J K."",·lit",t.,t1 "'t h~l' lritiat,ocl w ..ter , II... IrlI.Io"l'Ult- f"oc'~' p"'m d .'S tlo.. " ..·"'hroll..-. Wit" I"" '"YI"·",M ·· ;ilil,r ' lIl"'liU IITS, Ii~r tl.... l".Lu nll.k"l'U lo:' ,;hilul, tl... p;o."~ III limitt"<.J I~' Irolll. "" ·,,,bnuM· po'''. ,'1rati u" , not Io~' 101, ,,><1 lI""' . IR...lraw" fm ... WI" "... 1>.. .."d Rl'miw'h,," l y, J.: I" lr . linal hl...1 lI"w 11.,,,,1 ,,1....,'1lti..n uf 1,,",..lh.. ,,;;.bl.. ..,I..taIKTS. J. r1...rm . Pham...,:,,1.. 22:f>.m...M I. Ilr.O.)
Tritiated Water
6
Ethanol
Urea
o
•
o
•
t-
1.0 Intestinal Blood Flow (mUmin/g tissue)
Ribitol
1.0
CHAl'TEP8
I1S
H ,. Ko + log (Un-ioniZed concenlTOliOn) P 10 Ionized concentration P
2b
As h ~ lt l(l ) = 0. till' pl\n of a compound is til(' pI! at which tilt' uu-iouized and iOlli7J't1 romx-ut rutions an' equal. T Ilt' I' M is a characn-ristic of tilt' dn,~ (Fig. S-6). Consider, [or ('''Imp]t'. tln- alltil11;IKlllall i w' lrfari n. \ \'arfarin is all add with I'M -1 .8, i.t-.. equintolar conre-nt rutions of un- Ionbr-d am! ioni 7J't1 dmg exist in solution at p ll -I.R. Stal!'(1 d ilTt'n'ntl)", 50<J u fl h(' d m ~ is uu-iouized at th is pll. At one- pltunn luglu-r. 5 .8. 111(' roltin is to to I ill [a\ur of li lt' ioni7.l.'i.1 d mg: i.e., 10 out of II tot al parts or 9111 of till' dnlg now exists ill Ill(' ioni7.l.'t1 form . anti o nly 9'1 is IIn·ioni7.l.'t1. At Ollt' p l l uult IOWN than tilt' I'M . 3.S. Ilupt·n,'nl,.gl's ill till' ioui 7J'i.1 illlll lln -ioni7J'i.1 forms an ' 9 and 9 1, tilt' l'l 'II\'l'r~-' of those ill pH S.H. Fif.,' "n ' ').-'; Sllll\\~ d langt's in tilt' I)('n '('ul of IIn·iolli7.l.'l1 limg witll p I! for ,Ki tls of tlif· [l'n'nt 11M \"allit's. 111t' p ll r.mgt' l .u to S.Ot'n('lmlp asses values seen in th e ga...troinlestinal Irat1
Bases
AcidS
Strong
Weak
pKa
::1:, V , ,
.......-...... -"'-
•
, •, ---• •
Oii'
.,~,
--
-c,
" ,!l,
~
Weak
'-'
==..
Strong
'1--6.
n... I'M ,,.],,.~ n(
..;. IK·
;uKI " a' K:
.Imlt' ' '''Y wiclo·!:-·. SoI1M· .ln,1t' IOn' "mph"t.'rk- \"I. i.e' .. lhc·y h.>.. hnth "d.IK· "'Ill 1\;I., it;· rUll<1i..",.1 1:"'''1''
CHAPTER 8
116
t "llit. "-7.
\ '1'1'.\' .......~ ... ;. I, . !,""
,;l!,
..It ·r
~·
100
,11;111 't.Il• • ,.,. I,".. ~ .. "in.ml~· (.... "'
.J I Ii" d ",,·inlli,...I . ...., I' ll ,'il!,"", 1"1Vo1"'" 1.0 .,,<1 ~.tl,
1'" oI"...n,,1dlil/'Jo:I~ ill II..• fr..d i.." nll·i,,"i.....I ...·• ..... "'ill. pll fur ;/'/' "d ,1 ...1. ....· I' M ,..J'M· lit" "'il!.i" II..· r""!(t' of :l .Olo \ ,fl. :' fll " ..,~l lt ..· fr ·· Ii"" n".it .. 1"f '"f''' .I n 'fl~·r "" ...,. in..·,..· ...
,i,...
...,110
.,,1...-
1,~t1n 'l:t ·"
"·"wi". 1e
,
·"1....11"". tl.., .......~ "It,
· ..1 ,,, , I'll " .1.......1.."",
~
80
s ";;;
60
.~
pKa 10
=>
~ 40
.r
pKa 2
pKa B
pKa 5
20 2
3
4
5
6
7
B
pH
ptll1("(] and sl,uws lin p l! -tlep,r-udelll ah'oll rp liull. Only \\; 111 "Im ng,· r Ilu f pll Oil tI u- run-s IIf abM)'1)lioll and di strillllliun , TIl(' Iilt, I, · inlh ll' nl't' of p H 011 a mIl.' pmt" "s dt' llt'lItk hO\\'I'\'I'r, on wln-ntilt' ralt ' lim itatiun lit'S. O nly if rln- Iilllitatiun is in 1)('fIIwahility is an t'lTI't'1 nf p H 011 mh l'xpl't'tt '(l. If tI.... Iimila lioll is ill !)(.'rfUSioll, tI.... problem is nul OIW of movr-nu-nt of dnl~ Ilmlll,!!:l, lllt'lIlhmll('S and. tllt'rt'fllft" any variation ill pll is 1I 11 I ikl 'I~' to ha \'{' much t'lTt'(:1 on 1hl' mit ' p n It"{'ss, \ \ 'hen- IhI.' t'(luilihriu III lit's, III )\\l '\ x-r, is iml('1)('m il.'Ill (If wlMI pnlt''ss rutelimits II.... appn);(('I, t()\\-,m l t'Clllilih riu lIl. An :onlill,l!:ly, pI! is p n-dicn-d tn aITt'<.'t tilt' dt strt IJllliun (If all iClll i;r~lh l(, tim !!: ;(('m s.s ;1 nu-mbram- al ('fluil ihriu III ill all ('
PROT!lN BINDING ~ Iany d n l~s hillt lln pl.l\lIla pm!t'ills and tissllt' t,(lInp(IIIC'IIts (d ist'IISSI'(1 ill C hap. Ill ), s"d, hindin!!: ts R"\'c 'n>ih l(, ami Ilsu ally SCI rapid Ihal an e-quililmurn is c<>;tahli slll"ti wit hin milliSf.'(" mls, CUIISf."tIUl.'lJlly, 11)(' ;~s M I('i alt, ! (IJ(lum h and t1hSfIt'iall "t1 (ullho llm l) for ms of tlndm ~ {';m lx ' .lSSllllll,l lo lit, al l'(luilihrium al ulIlinw s 'Ultl lllltl('r \i rt"all,. all t'ift'lllll"I'U1t'(·S. O nl,. unbound d m~ is Iholl,!!:l.t to II(' J?;t'lw mll,. (·.11);1111" u f p'Lssill,!!: 11m ",!!:" nlt'lIllmu l('s, rlu- pmlt'in -Iltllllltl for m IIt'ill,!!: h ltl lal"J?:t' 10 do MI. -11u- inllul 'IIt" uf p ml( 'in hilltlill,!!: UII lIlt' ra lt' o f I1IU\'l'lIIl'lI1 tlm ltl~h il IlIt'm lmuw t';m lit, \il'\\l"t l ill mllt'l, lilt' \;.11I" W;IY ,\-" llml of lilt' inllu('''('' of p l l u u tltt' IIIO\'l'III('nl o f wt';lk adds allt ll );~M''' . Hul l. himl in~ allt! ion i /~lt i oll a n ' ,i rt llall,. insla lll;uwolls n 'atiiulIs, \\i lh uuly 11I11' Sl'lt"l'i" s (UUho lilltl , u,, - iun i /~ '(1 form ) ('apa M(· of Ira \"l' n>in,!!: nlt'mhr.ult' s. If t"t' n ' is a IlC 'r fusinll Iimilalioll , c!i\MIt'i"lioll (If lIlt'
117
CI-tAPTH 8
hu um l d m g am i di ffusion uf lin- unbound d r ug lh mll ~h tilt' membran e mus t occu r so raptdlythat ra tes of dd h·t'l)· and transport are t'<{IJa1. 11ll1s, all alt eration in p rolt'i ll conten t is not expected to alTt'l1: rate at a gi\"t'lll'O Jll'('nlraliuJI . If p -rmeabihty ts ratt'-lillliling, littlt ' uf tilt' d rug p rt'sl'Il!t'l1 IlIUW S into lilt' tissue . For a ~,"('n rate o f delivery. altered pr otein I )i fl(!i ll ~, h~'
RIVIRS IBII NATU RI OF TRANSPORT It is importan t tu n-mcmber th at dmg transport is gl'm'r.tll)' lndin-ctioual. Om- tends, for the ~ast mi Jlft'sti nal lra(1 as betng unidin-ct lonal. 1'\o nnally, with \"t' r:' higll coucontrunons o f d rug placed int o Ibe ga.~t roi ll t t'st i llal l rad , Iollo\sing ora l udnunistration . tin- net ran- o f tra nsport is loward blood in mesenteric ca pillam-s. l low eve r. important applil"ltiolls ca n be mmle of transpo rt in the oppos it e dtn-ct ion . For e-xample- rq )('ah 'l! oral administratio n of charcoal can hast en removal Irom ti lt' hod)' o f d m gs sueh us tligoxin, phenylbutazone. phenobarbital. and digitoxin in cases tlf dmg U\l' n IUSl', Ut'l',ltISl' o f extenstw ad.sorp tiun uf d m g to charcoal, tilt' lu nn-n of tilt' ga.stm in< tesrinul tract ads as a sin k for removal o f d m g fnnn blood . In this case, th e site o f tmn sft'T may 1M.' n-strict ed to oll l~' a small regi on of the- ga.stmintest inal trlll1: or Illlly apply to a milch lary.:t'r un-a. TIlt' rest rict ion depends Oil th e dist ribut ion o f charcoal alo ng tlit, gol~t mi n !t's . tinal tract . E\'('II with t.ump lt·tt· d istributiollof charcoal. whether till' ove rall tran sfer Irorn hlo(xl to ~ I t luuu-n is p~,' rfusi oll rute -lhmted or 1I0t depe-nds on the pt'nm'ab ility of tilt' various ti mdion alll1 t' lIIlmul(' s along tilt' It'n gth of Ihl' gnt a.. \\"{'II a." Oil blond fluw to ti lt' S(' various silt's. As prt'\iuusly statecl, lilt' concepts o f th is chapte-ron p;lsslige of drugs across me mbranes art' iIIlIM.Jrtalit to all undcrstandill ~ of moee ment of drugs into, within . am! out of the b(xl)". In lilt' next th n-e chapters . tlu-se concepts are mccrporated \\i th ot he r p rind pll's tlt.'aHllg \\i tb d mg absorption. distribut lou. am i elimination. t' ~ l1I pl t', 10 think of d n ll{ absorption in
STUDY PROBLIMS (An ~wer~
10 Study Problems ore in Appendix II.J
I, Dt'fillt, till' terms: pol\ siw d iffusion, passtcc factlttatcd diffusion. active tran sport, and pt,T!tw,11,ility. 2. How accurate art' ('
111
CHAPrER 8
Teltle "'1. Iffect . . .~ ........ &(th,.... CII.". .' ...... H_H.11fe (Heunl
......._ ......Itw..
36:l: 13
03
:!;
7
"""""I ,5 M ('JI".",, ~ ' .~.JD .<>"'IT""'i.lIG ~"""'<J"'_<J ~."*"",W"""",*,,,,_~doMocio<~ etoooa:d jNM, 25/ 31000l-3 10ll 1QS4 .179 d ~ .. 70 ..... cJ M ooob«lI ..-;
a. KIllMing tha t tilt' \'o IUII II" of d istri butio ll o f ph t'IlOha rb ital is I)..~'j I A~. ('ak1,lah' tllC' clearance o f phenobarbnul into til(' alinw llllll)' canal during t reatmen t with d Mrt'tl;11. lIinl: C I. (d uring In 'a l lllt' lll ) "" C L (no frt'af llw lI l ) + C I. (hy d lan:: oal ).
h. 111t'
ck-uruncc
value delefmillt'(l in
~UM
should apply us wdl to
lIIo n ' lIIt'II1 o f
dmg
Irom the hmwu o f t ht· ~a:~I ",i lltt-st i llal l m<:t into tln- h((JlMlsl n -'lIn. If til(" llIajori l~' of d r ug rt'1Il1M11 and ahso rptlon O{'(1 Irs i ll Ill(' small inlt'stint>, es timah ' the- hiM·lifc· a.'i..'\(Ki all't1 wit h abso rption wln-n IU L of lIuid is in th l' small mtc sunc. Fo r th is pr obk-m. concetve rlu- small inll ·slillt· as iI sillJ?,lt' l11lllpartlllt'llt .
ABSORPTION
OBJICTIVIS The reader win be able 10: 1 Describe !he sepsinvolved in !he ceclabsorption of a drug 2 . Distinguish between diuoluhon and pelmeability ,ote-limilalioo!i in ob!orption . 3 AntiCipate !he influence 01 ~iCOChemicol prope!tie!i of a drug on ,ts ob5orplion from diffetenlsile5 of odminislfolioo.
4 . Anlicipole!he role 01 goslric en"plying and intestinal trom;1 in thego!Jl'oinll»llnol absorption of a drug, with pCJIlIcular relereoce to !he ~lCochemicol pt'op9fll8S of !he drug and its
dc»oge lam.
5 . tis! the Ioebs Influencing d,oouhon rale of a dll'9 . 6 . Descnbe ibe inlluence 01 decrecsed permeability and surface oreo along !he i~lf101IfOCI on the pedcercoce of ool COflslanl"fole release 5~5 in vr.o.
Drugs an' m os t fn.'(IIlt·lltly ad minish·n ..1 (·xt r..m L<;(.·ul arly. Tilt' majority a rt" Intended to ali S)"Stt' lIlk'l.tlly. and for these, ahsn rp tilJlI is a p n >rt"Clu isitl' fnr ad h it)', Dd ar s or los ses o f 11m ", dllrill ~ abs orpnon may cont ribut e to , .uiahilil)' ill d n l~ rt'sl")(lIlst· and. ul't'asiuna ll)', m ay
result in fajlun- of dmg tlll·rapy . It is primarily in thts e urn-xt. us 1I sou rce of va riahilily ill systemic Tespm lst' am i a.s a means of (111ltm lling the conceut rat ion-time p m fil(' of d m g in the body. that abscrp non is conskh-n -dlu-n- and th mll gl.oul tln- n-mainder o f the hook II should I., k('P1 in mind, however, that ('\ '('11 for IlJost ' d nags jnte-nded to act IOC'lllly ( '.g.. mydrialil's . local am-sthcncs , IIlL~al d (>(1J1lgt'slallt s, topi ("11 lI~('n ts , and ,!l'mso l Immd ll. li· lators], 1lI ( l\'('IlW IlI o f d m~ From till' sih' of app!i<"lIlioll lo tilt' s)"sk mil' ci rculanou inllut'Ill1' S tillw of onset. intensuv. am i dll rali ull of t·fTt>(i . 11lis chapte-r ("lllst.,t llt, o m l llKMlt· o f ad m inislrat inll is tilt' mo st prevalent for sysh 'rnil"llly a(i iu ~ d n'gs, hut a]S(1 lx-cause it iIIustmh's lIlallY sou rces (If variallilil)' t'Il<'1 11I1ltt' R11 ill dmg allSorp lillll. Fi~u rt.' 9- 1 depict s 11ll' mnm-mus slt' ps il\\l ll\l'd in the " hso lVtiull of a llmg g1wu nT:.llly. Ilt'i ug a complex struct u re. lIIallY uuatmnic and ph~'SioloW(' fadOl'S afT("C..1 the ove-rall mit' and extent of dnlJt abstJ'11tiuII Fnnn till' gil.s tminlt'sl illal lmd . maL.i ll~ a pR >(1s(' IjUlllllitllli\'1' pn'llid iull tliffk llit . XOIwt!1('ll'ss. much can lx' IIIJ(!l·n;I{M.! lIlid appn"C.1. 11lt"C.l of tht· (" ,'nls (x>('1 l ni n~ al this lim! other sites of ahsorpt km . Ahsorption is fanJR"C.! h(>('llUSt' tilt' I . JtI~· ads 1I.S a b ~l' sillk. A cone..-nt ra nou Wadi t·nl is pn·st.'111 until \i l111all, - no dm ~ re mains 10 I.· absor bed. Till' gnuli('lIt is Iwulltai ll("C.l lolIgl' f. IIU' lafJtt'f lilt, \'(1111 111(' of di st rilmt iull of III(' d nJ ~. 119
120
CHAPTERQ
P;,-~ ..ag(' (If dn ,~ thnmgh tln- mem branes di\itling tlu- absorption sln - from thr- hlood is a pn-n-quisite for a!Jsc)'lltioll to occur. Til
ABSORPTION FROM SOLUTION St'\l'ml ph~"li i(Jl()¢c am i ph)'sim l factors that dt'l t'nllillt, movement of dnll{ tlmlll gli membrum-s han ' ht'('11 t1iS("l.lsst'(l ~t'lle rall}' iu Chap. S. lncluded a mo ll~ t1WIII an- the physicochemica l properties of tilt' molecule, Ihl' uatun- of the uu-mhraue, perfusion, ali(I pll . These f,,{'ton; ; 1II t! oth ers are 1I0W {'ollsidt'n"{l \\; Ih respect tn drug eleorptlon.
Gastrointestinal Absorption In al'(unl;u ln ' witl. the p O'l li{1ion of ti lt' p i t partition h}]x) tlJesis, weak adds an'
ah~orh('l l
rap idly From lilt' stomach at pi 1 t .Otha n at p H H.D, and tilt' co nw J"S(' holtL~ for weak haw-s. ;\ bso rp tioll of adds. hO\\'t...r-r. is always much f'l\ ft'r from the I('!is acidic small Intestillt· (p ll 6.6 to 7.5 ) than from tilt' stomach (Fig. 9-2 ). 111t'S(' llppan'nll)' l,(lTlfli{1 inR obser\".IliOIlS run lit· n'l'(JlIl; lt'l l. Surfact· an-a . permeability, and for perfusio n rate-l tmued absorptlou. h loc ltl flow an- imp ortan t determinants o f tilt' rapidity o f absorption. TI ll' intestine, l's lx'l'ially tln- small mtesnne, is fa\u n 'l l o n all accounts. T he tot al ah sorpti\l' urea of tilt' small illh·sl ilw. l11111post 'll lal).:t'ly of nucru..i lli, ha~ lx-cn calculated to he alx llli 20l} ~ 1 2. llml an t'slima! l'{l I L of blood p'L'iseS t hrull~h the intes tina] l'llpillarit'S l';lCh minute. TIll' (1Irn' sl,)(l1It1 i ll ~ c sttma tes for tl.t' stOlllad l art" nnl)' I ~l i: ami 150 JIl l Imin . TIle pt-' nllt'llhilil)' 111 0 rt'
Gut Wall
Portal
liver
Vein To Site of Measurement
Metabolism
Metabolism
To Feces t 'IK' "...1. :\ ,Imjl., \.'1>...II .l. .... .lid. " 'K'(Ml ll h' n .. ....·r..l l...rrirn ..,KI Sl iM uf 10-",. in ito .... 1'.....Ii.,] ItMM"" ... ,,1 .h llillit jl.oL'ln'illlt"Ii " ..I ..I"'''l lt i''fI. 1>i.." .I"h"u. .. l' n·""'llIi'i' .. ' " " MM·" ... "I ......"'. JI:Ill "'all , i. tI... li..... '
,Iv·
121
CHAPTERQ
of lilt' illh'siinal llll' mh nlllt"s 10 dm~s lIlay aisc i lJol: ' fi!:n'ah'r than tlMI nf till' stulllat..h. 11wSl.' iucn-ases ill surfat" un-a, !>l;·rmt'ahility. ami blood flo,", more than t'llllpl'IlSllh! fur tludt"t'n·:t\t "ll fr.lt1illn of un -iollizt"ll add ill the Inu-sttm-. Indee-d, the ahscl'l,tiult of all ("( I m pounds. Iw tltl')" adds, hav-s. or neutral compound s. is Faster From lilt' (small) inh·sti.w than [rmn th e slo tllad l. Bt"t'all sc' absorption is J;': rl' alt"f in the small inl l·stim·. tln - ran - of ~.t\ t ril' t'lllpt}in~ is a l"l llltmllin).t sh'P ill III(' SIW('l1 o f dOl ~ ahsorptiou. Gast ric E m pt)·i n~. ( ; 'l~lrit· t' lI1pt)i ll~ of liqui ds is app mximall'iy ...x-ro-onh-r. Food. cspl'l'ially fat , slows l:'l\ l rit· (· lIljll}i ll~. whk l. expl.dus why t1m~ an' Frequently n "t'OlIlllw nd t"(l 10 Iw t.lkt·1l nil an r-tuptv stomach when a rapi d ouset of at1inll is desired. Dmgs that inHUt'II(,(' J;':asl ric ('lI1 pt}i n~ al.\u alTt"t1 tilt" mh' of lIhscllVlinli of urln-r dnt ~S ( FiV;. 9-1). Hdt'ltliort o f dOl!! in Iht' stomach i n(·n" t~·s tln- percentage o f a d ose ahso rlJol:'l1 t1Jnltt~h tl ll' g.tsl ric muco sa. hil i usually 111(' majority of d m~ is still absorl Jol: 'l1 t1 JnJtl ~il ti lt· int estiual t·l' illlt'litlllt. lit litis Hog.m !. lilt' stu llIad l lIlay 1>1;' , it'WI'l1 as a rt."[Xl'iitory o rga ll From \\~I kh pulw s of t1 nl ~ an' ('jt"(1I'l1 h}· lw ri.stalsis onto the absorption sil('s in ti lt· smal l inl t'slinl·. Intt"sliu al Ah o;oJ"p lin u . Th ruu ghuut its It·ll~h . tltt· illh'sti ll(' va ries ill its lltllltif
t·l p:. 9 - 2 . 1>" ' l' il (";/,1I 1·...·; ro" "'1' 1I1 f~,'ori ,,~ ;/, jI;rt'll!t'r po·n....,I;/,K!'· of " " _jo ,, in ..1,lruK- "' ...."l>t io. , .. f 'l;I,/iI..,fit- ..., 01 (, ' M 3) I. ,10.""''1' frunt tI,t' ...\1
i Mo,lifM..1frum I>ol,," it•. J T.. HIlI"I'" S F.. l>itT.. rt. I ~ \\' .. suiOl". F..C:. ;01..1 s";,,t<..~·. I X .: I>",~ a1.. "''1ltio.., I, ., ,, ill . it" ..... ~nt 1t,<-hU" IIl" ~i,·lot" 'l: n-"' I
Stomach, pH3
,,,,,,,·r.)
Intestine, pH6
o
20
15
40 Minutes
," ' ,,t "
,,
, ,,
80
60
t·la . 9-.1. Slo.",,;,,~ ~;I,.Irit.· ""'I't~i"lo\ I~' pn.. l>4Illl.. -I.i'''' (3111 "'K i .•'.) . It...... II.......II· tI( a1.. !It>rplit., ,,( .....i .. ' l1..·" (15C1O "'K) lnriuh'r" ..1onoll)'; lI. 22.~. '..r-ho·" i. ""•." .. It....• ( - -l. M... lud " ,...l1nitl.- ( I ll 1I1~ h '.). whil-l. h....I t.. u~. llit· "II1I~l"~ 1.....It·". tl.., ..I>">tp! it,n o( Ol/.'{"('
m"..
,,
,,
, ,,, ,,
,,
,,
,
.... ., ~
-.
a ",I"np h .." (---I ( I ",(I I. • 6 .6 1.l ~1) . !RI.,I.."",n rn,," ~ illlmo. 1-, 1I.·... bnll.. H e..
,
,
o
2
3 Hours
4
5
T<>t lnll. 1'.• "' ..11·" .....,(1. I ~ I', : 11..nn>Ol.t1t..;~-.J tI .. "bllt...."., of 1I.",Ir;'" " '" IIt~;"l/;' Eff....1. oi I'n'P"'nll",li'''' ",..I It..i od"I' ra"'itlt· olt par· at......",,,1 (al... I."'i ""I'I"," ) al.. "rl'tlm,. Hr . M•..t. J.• h\\7.....'»\. Hli3 .)
122
amlla~t' i ll{l ...lilll· ~·par.d l .. 1 hy tlw ih-ocecal j llll(:tinU. Snrf'K't· an-a Ill" umt It·IIJ..'1h tit·· (·n 'a.<;.(.,;; (mill the-
alltMlIld.. wtth an al'A )"i,: mic·T1Jflnnt. TIlt" IllFoUl p i I. 6 .6 ill t he' pn":illlal s mal l in h"lOt ilU' rhiuJ;:: 10 7..S ill IIII' It"nnilla! ik·lIll1. falls !iharpl~' to 6.4 at lh,>start of ti M' 1"('(11111 I.·fun· ll llall~' rhilll: In 7.0 in Ill(" d,-<;(.'(·m ling ('okm . Tr.ms it ti llK' of lilah-rial s is an"lm l3 to -I lir in tll(·
slII;.1I inh...tuw alltl (n )ln 10 In 24 hr or eve-n lun ~t'r ill tlll· la~l· huw..l . Ahhuu gfa th('!\t.· and utllN l'Ulllplt ''\iti.~ 11I;11.:.· pn"d !\(' (I" antita ti\"t' pwdif:tiull u f inh"'tilloJ dm!: ah\ol'r ptiun di f· fK'llt. v-veral ""Iwral fl"lm.·r-IIM'!li;I!t·c1 pnx,"S"'f"S. ",tlt'tht- r \ l.a the transeellular nr poardl"t'lIl1w reete. 11M" ( "''{' n'i(\(' in p , S." i~ !lot'!"n d.\ a (k'<.Tt·it.\.t' in tI ~ IJ nt-til-s uf ainurptiull wl M '1I dnl ~ ti( "' Irom tilt' 111 1111'11 i.. po'rfll!>ilill mlt-·limi h-d ( Fi~. S-S . p . II -H. UIJ(...· r tlK'!\(· c.'ullflihul1\, fl\"t'r.J1 ~;.L\t ric.' 1·IIlIlt)i lll.t " 'Mlk l ra te.. limit :lh'"0'l)ltun fn llll an oral \Olutiun. As shown in Fi ~. S-5, at an)" UIlI' ..itt· alu lIJ.: 11M' inlt...;tirM·. ill this (""d-~' tilt' jejun um . ..mal l mnk"l,llt... pt.· mwalt' mo n' fn '!' ly tha n L.rgl·r (11M... . nit· i\'SII(' (If In(tk'(,,Iar ..tze is (Mrtic."Ia.~· important for pol ar d m lt'. n M"5ot" \ lIlntillK' ''' IIMI\1' 1l;lr..,· " "larl~· \ia thl ' ti"ht fUIJ(.'t ilNl\ Iot·t\lol " ·III-pitlM·lial ('1·Il... Pt·nrwa hili l)· ,tllpl' ;' ni In (Imp n IT shotT I)-' with flM.It'<.'lla.r \\loj ~flb a1. 1\1' 3,'50 Wmo !,·. \lolt'(, 11ar sb.l· ha.\
n,i,
500 Stomach
400
Jejunum
Cecum
100
o o
8
4
12
Hours 1-lJ:. Y-t . n..· ","~I "li """' lrwl .J >tpIi<", ..r,..."t>clillt· I....... \0, 110 .. It - .. I' "I1>1.. -..Ii<." .. 1.....11 ....· Ih.· n_n pLoo.1\lI ......•..I...t .. ... -III1..• pn.lil. ....i ' "1101"..• ,>1_.,.,•• 1;«1.., pI..~ lU' 1'......... ~"Ii,'" l6 "'I.) (..,I"':" i,'II: 1.50 "'It ..( r"'''I.. li ,,,' I,~.I ". ~II. ,", Io. i" l" II 1""....", . -'. ;"';" " 01 '" t & 1. .... 1 11, •• -, ,i n¢'1..>1"',I_n. . ..... Ilolt" "",I~ 1,,1 , n ", ~ .It.." t ...h",'i>~ J_>tpIiIR".. lP· S., ) p". I'''i ~ h 10....... in Ihr ....... dlolh in " \t , !I ",••11 ;"10"'''..·. \:.,. " .. II ..t-"l""'" IIf .....'I>di · o:-fTf'(·ti ·~'I't'"._ (in Irnni dt.-I'I" ph-l"'" 3 hr hm lM.nl'h lho· \t l..' ...... ' II'" ;rj "n. ... ..,. 11".,e, tI... druil; i lIp101t~ 1 Lot IF - U6 . ,w.. not "", tl l ...q:. "''''lI: tl... tl..· , ,,wll i.. l h ...· " 11,,· " loIj.. t" til . ' of .l- orrt" MI ...1..... ralll"b I. lioILrn '~" (" 01••",,,,01 ("111I w ,II..." .. Sl t-., n"l..-<. (; t:.. II...,.., . W.. Il.on . " · 11 .. II..rman.. . n J, '.. n'rbn . T., . ...1 11..... I.J , I" ft......... IIf ~""-.; "I~i .. J "t... i ,In l( . I.-In..-ry . MI If.... ..I"'''J'f''''' ~"",in. IIf 'an....L.... 11wrm. H.r. . flIIYlI-I IY-t .
'I,
Jy.J'~
I
1)(' rIllt ,,,hil it~· fur lipoph ilic d mWi' which lr.lSV('Nt' ImnM'f.'lIu!arly. The ultimate limit 10 pt' rIlwahility is Si7.t', llOWt'H·r. 111l1S, la~(' polypt' ptid('S, proteins , and ot he r macmmok-cular drugs an ' \i rtllall~' un able to p
k-ss of all ('Ired HII
Fur t'\1IlIIplt'. if51I'l o f lilt' d n lg is Insl at {' ;I('" sltop. Ihl' hit li.I\1u lahil i ~· o f the d n lg, measured syslt' mali('ally, would lit' 0.5 X 0.5 X 0.5 or 12.5%, Xote that the d rug can lit' n-nden-d totally nnll!']lti un t)f 1I's,'i pt'nnt';,hlt" W ,IIt,ntll~· l'M l];tr, d mlt" slill primarily t)("('lIrs \\i lhin tilt' sma ll illh'stint' bllt is unlikel)' to bl;' l'Omplt'l(, \\i thi n tilt' limilt'll 2- 10 -1-llr tr.msil Ill'ritM!. E\idt'II("(' SIlPl'M lrl illg this lIolioll is pn " idt'(! \\ith tilt' 1I 1 -a ll ta~olli st ran itid im'. Thh rd alin 'ly I'M lIar slahlt' l'IIlll'M llilld i ~ ;ulllosl totally I'xert'It'(l lIlldm ngt'l l wllt'll ¢ \"t'll ill'ran 'Il(l1 l s l~·. \\1lt'n W\"t'll o mll)", 6U% is ahSllrllt"d hilt all \\i thin the first ,'3 to -1 hr afh 'r atiministratillll (Fil!:. 9--1); tht' n '.'it is Il'(' '''t'f('t l lllll'hallgtoc i in ft'l,,('S, f.\itlt'lIlly, w ry littlt, ra nitidi nt' is ah'iorllt't l fmlll tilt' la~t' in!l'sti nt' ("'l'n l hou~h d m /;?; mn lit, then' fo r up to 2-1 hr. Tahle 9- 1 lists repn'st'lltalin' t1 rt1~S for whieh om l hi(li.l\'aibbilil)· is n'f)' !ow (0.1 10 14%), most likt'iy dill' 10 1'M lor inlt'sti n;a) Ill'mll'ah ilit)· \ti lll nU1'i 1 of that ahSllr!)('1! ha\i nl!: (It"('ufrt 'fl \\i thill ,Il(' small inlt'slim'. 111t'd n lgs shan:' tli€'t'()1Il1ll0!l pml)('rti('s of I)('ing l'M l!ar
124
and. with tilt' exception of pyri t!oslig milll', IT-Iatin·ly lar~t· (mo](,(.1,lar wt' i~h l ~rt'aft>r than .too Wmo1d. I'yridustigmi llt· is a quate rnary ammonium ('('lIlpound. which Illil~' explain its low hioa\~lilabilit)' dt·spilt· its smallmolecular wt'i ~hl ( 18 1 Wlllo!e). ~t ()sl o f the compounds lislet! in T able 9--1 cannot he ~i\.t" 1l orally for t'lTl'{.1 i\'l' s)ost('mic atti' il)': they mustlx- gh,("11 parenterally. Finally. the n- an ' small molecular wt' igIJI, 2(X) 10 ;].'j() WIIIO]t' , potu dn l ~s fIJ r wllk !. ahsorptiou, alt h()ll~h Inco mp lete (50 to ~}% ) , is sumdt'lIl1y hi~h to n-nch-r them useful ~\'l'n o rally. 11Il'S(' include'<:inw titlilll'. ranitkliue-, h)l lmd lOmthiazidt·. and utcnolol. As with ramtidtne, t h(lll~h . tht· small inf('slillt' is Iikl'1)' to ht' the predonunant sitt' of ab sorptmn. TIlt' rect um has a small SUrf,K'(' un -a. and a d m~ WH'n ft"d ally is nol al wa~'S n -tatned for a sufficient Icnl-.rtt. of tlme 10 ensure complete abso rption. :-':0 lillie limitatioll exist s filf a dm~ injt'<.1('(! into muscle, subcutaneous tissue, and IIII)..st other stte s wirhin tlu- hody; complete absorp tion is anticipated unles s des truct ion 11I.'('Urs 1)(' ,"l ,( ' U silt· o f ad ministm lion ami S)-'S!l' mie d n 11lulion. (.'ompt't irag RpCJcl imlll, Any react ion thai ('f lll l p '''tc ' S \\i lh a!Jsc)'ll liulI lllay f{"( IUI'f.' IllI" oral hiOiI\1ulahili ty of a 11m,!!;. Tahh- 9-2 lists va rious reac tions Ihal 1', 1Il 1J('(llr ",i tlJiu lilt' ~st mi ll i esti nal 11';1l'1 . Hcact tons can he ho tl. t'll~l n;llie and lJUll{'Il ~'ll\at il-, Add hydmlysis is a com mon nonenzymatic react ion. E nzym es in tilt" in testinal cptthehum and wit hin IllI' inh'stinal microtloru. wlaieh uormully rt'side in tln- largt' bowel, lllt'tal )(llilJ:' SClIIll' drtlh~ . TIlt" reaction products an' oftell Inactiw or less potent than til{' pa n 'n t moh-cuh- lun-rac tions "'i lh <.'tmslih wllts o f lilt' ~'lsi roi ll l ('st i nai ll uid.s al.so tll.'('ur ; til{' fes ult may 1)(' low d n ,,!!; hiull\"ailabi lity. For example, mn- reason why tt"l l';l<"yd iIW is in('ulIlpli't{,ly absc)rl)('f.1 when coadnuntste red with milk and wi th certain antacid s is that this antibiotil' For ms Sp
Dew,. ",_1"1 Lew 0-1 .1....,.11... 111.., 11Hrt I.
'.We 9-1. P.-r 1....tI_1 P
.~
Genlomi(:ln
Amil.ocin
,
c.
11-2.
Co,ben,CIII,n
Neomyc,n
Ce!omondole Ce!orol,n
Pyricbt'gmine 5rreplOlT¥:: l n
CeIotoxlme Ceha.zid,me
Voncomycin
T~opIon,n
..p,.._........._tl_.
...... ~t.:o...
wl
'- D-. AIt...-ptl_ ........1
Comple>
Owe ..
III.,-
_
I...... o......I .....tI ...1T...ct 11Hrt
TetrocycJine
Conl"'9CJlIQll
--"'"
SuIlocOfllugohOfl Glucu'Ofl;OOt;on
Hyd'~$
'''''''00''''''
~""
LOM 01 och\/lly: pl'oducllnocti\/e LOM 01 ocrl\/Ily product inoc~ve toM 01 OCrl\/lly gIven wllh 0 penpbercl dopa deca rboxylo~ Inh,bolOf 10 'educe go$llOmleSllnol rneIOboIl$II'\
k~
LO<\$ 01 OC~\/IIy : ptcduc1lnoc;11ve LOM 01 ocrMIy product iflOC~ve Prcdccrs (d>g11OX1ool have ecucbe OCf1\/rly
Enzymatic
Sol.cylic cod formed, cce-e onrl~nflommotorycompound Acr,ve ompi<:illin formed pl\/OmplCl\l,n (e~) 1$ IflOC11ve Lo» 01 ocrl\/IIy: producllnoc 1ive LO$$ 01 ocr,\/,Iy product Ie» ccn-e Insended /of cccr (,nresr'nol) on'~mflommolOfy OCIIQll: poreer drug may have someocr,\/,Iy: ceodcct, 5-omiflO$Qkyli(:
o.lClorlQll ~ed uction Imi(:,oiIoml
ccd ocnve Ad loOfplion 10 choieslyfomlne: cdsobed morenol not c bsobed
CHAPTU 9
'25
in.t::ly su!uh l(' ('fllllp!('X('S will. lilt" poljvak-ut cation {e ..t::.• C a 2+, }-'l,3+ and :\.1 1+) conta nu-d in tlll' st' prepar ation s. TI lt' eo mp l('xities th at Ol"('ur ill d w prt.dudl' accurate prt'1lictioll of tilt' contri lmt iou of a ('flmp('tin ~ n ';l{1ion to d''1: r('lL''l'11 bioa\lIi1abi lif)', S omet i mes tilt' problem of Incomplete absorption rnn h(' l'in'u lIl\'('nll"(1hy physit-ally pron-cnng the d rug from destmctlou in Ihe slollla{'h (s('t · enteric (Uatill~ di scussion. p , 36 ) or I» ' syn thesta ng a mon- sl;lble deri vati\"(', which is couwrtcd to tilt' uct ive 1I101(,(11Il' within th e body. Similarly, to euhauce absorpncn, ilion ' !)('rnll'abl,' deri vath"t"!> an ' made, which are mpidly ("()JIvl'rt('1110 Ill(' adin' molecule. oftI'll du rin.t:: passa.t::e through the intes tinal wall. For example, absorption of Iht, polar anti hiot k amp idllill is illl'fllllplt'f(" Its sys temic dd i\l'f)' is Improved substa ntially by adlII in ish'riTl~ a ilion ' lipophilit, and permeable inactive este r prtK1m~, pivampiedliu. Tluh~ 'tlrol ys i s o f tlris ('StN wit hin tht, inn-stmal wall is so rapid that ulll~' ampicillin is t1('h'(1('11 in tht' l'i rt'ulatiun . D r-n vativr-s. such ;l\ pivampicillin. an- ~(,'l('r-dlly refem-d to as 1Jmd",1!. ~ , ' lS t1l1'y an- ph arnlill'fllc'¢lM dlly inacti ve. 1If'I Kltic Extract ion, Aspirin ( a{1:tyl sal k~..lie add) is om- of till' first Sp ltllt'lk prodrugs. It was lIlarkl'l ('11 at the tu m o f tlu- ("('lItUl)' to overcome the unpl easant taste and tilt' gast rotn tes nual irritation ass ociated with lilt' pan-n l d rug, salk ,..lie add. Aspi rin W1l~ o ri¢ nally thought to hI' inadin', I)('ing des igned to be rapidly h)"tlmIF '('l1 wi lhi n the hndy to salit"!i{' add. Only slll)';('(III('ntly was aspirin shown to he pharmacologically adiw, Y(Ot tilt" ori¢nal dt'sign wor k('11; upon ingt'stioll, aspirin. a labile es te r. is r.tpid l)' h)'tlml)·J'.t'lI, particularly hy ('.S It' fi N'S in the hw r. Ind(,,( '1I, Ilt'patk lJytl mlysis is so rapid that a siJ".(';lhlt' fraction of aspirin is {1111\l,rt('11 to salk)'!i{' aoid in a si n~I(' pa~sa!-,:(' th rough th e liver, n's ultill~ in a substantial "first -p ass d T('('I ," 1)OII-:S tllat showa suhs tautra l first-pass ('ff£'ct d uo to Ilt'p;ltk elimination art' listed in T ah lt' 9--.1. Apart [n uu th is feature, tlll'y have httle in common. TIll'" are of d iw I'Sl' chemical structu re . PI)S"l·s.~ tliffe l't' llt pharmacologic act ivitie s, am i an ' llwtaholiJ".t'l1 via a num ber of pat hways. \\1 It'l1 tilt' llwlaho lih' (S) formed durr ng tilt' first pas s tIlrtm g:h the lin 'r is les s po ten t th all the parent t1m~, tile 0 ...a1 dose is la~ef than the i.v. or t.m. dost, n-quln-d to aclik-ve tilt' ...11111' tlu-rape-uttc effect . 11 1 i.~ occurs for lIlallYof tilt" t1m ~ listed ill Tahlt' 9--3, In ~ l lll(, instances . t' .~. , i~lp mlen'nol. lu-patic extraction is so hi~h us to ('Sst'lIliall)' precludo tl\(' o rul m utt', Ih-n-. nn amount of pbunuaceuucal fonllu latioll he lps. Euher till' dnlg mu st ht· gh '('11 by a parenteral mute, o r it must 1)(· discarded in favor of another drug {'illld icl"tt" A method of l'stimaling tilt' mlll;imumlikeh· d, '('n'RS(' in oral h ina\"ailahi lit\' due to this firstp.lSS ('ff('11 is diS{'lI~S('11 in Chap. I I, Elimi;lat ioli. •
..pre
, • .,1. 9-3. .......Iv.· ..n'
H
v. Drve. lltewl~ Lew 0-1 al_v-IJ..,lIlty"'" I. D.e .. lc Ilf........_·
Alpteoolol
Hydrobzllle
NaltteXOlle
,Am,'rrptyliroe
Imip
~mi ne
1$Op"~enoI
Chlormeth'ozole Chlorpto....o::wroe Cy1o'obine Desiptom,ne
I$o$orbode d,n'"o'"
De~ltopropo~
D,hyd'oe
Nico/cI;pine NiGQI,ne
Kelomine
N,!ed'p;ne
tobelolol lidoca'ne
Niltogfyce
lorca inide
f'henoxet,n
Me«:aplop,mne
PenklZocine Pento. ,lylIine
Do.epin
~ida",
Do.O'vbicin
Meloprolol
PrOptonolol
Enco jnide EWodioi
Morph ine Nolb..oph ine
ScopoIam,roe
5.fluorOUIOCil
Naloxone
Vero pom,j
Of . 05 ~ "'. on <>-o}O
'''doped<>'''
0 1- 25. 10 8<1
5 M .....ell."... I N f .1l'JIO" .........".",
T"""",,...
ea... CON.:..... .....eldonocol ~ Cl.-. """'_ _
CHAPl£ ~ Q
12.
A\'ni di ll~ first P;L~ S t h n l\l~h tilt" liverpnlhallly {"plains mos t (If tilt, ad ivily of lI i t n ~l~l"t'ri li adrn inislNI,<1 s ll hl i ll~lIally fur all acu n-
svs te-ruicallv il,
i ll
h!ood an ' link weuklv ad
t't·rt,;in d n.·l llTl~tmll't~ may n',wh couceutrations hi~h {'l1011~h
nvt tv.
TIlt'
in'
hut umk-r
Ie; l1 J11 l ri i lll lt · III overall ,1(>-
n-ctal mlllt' hils a (I{'fi n ite atl\1U1ta~t ' over lilt' oral mult · for d m j..'S dt-slmyt'(l hy
~'I.' l ric ad tlity or
hy ('1I1)111(, S in tht· illh -stillal wall and m il ' m lill m . I'nh·ntially. rln- rt't1ill mnte- may illsu pa rtially (t'(ltll,(' first-pas s Ilt'patit, loss. Part o f 111I' n -otal hlund sll pp l~"
Jlilrt il·ular ly Ih,· Iufenor and midd l,· hl'1Il0ITI.oidai vein s, h~ 11;L\st·s tln- Ilt'patil' portal circulnnon amI dUlllp s di (('t11~' into ti lt' inferior vena l'u\,a. " l'h i,·, ill !!: a (('p mdul'ihle biuavuilability, whic h is Imp ortant in dm ~ IIll'mpy. 1I1 i1~' 1)(· d ifTkult . how,'\ "('r, silll'(' h io
Absorption from Intramyscvlar ond SuIK"toneous Sites Tile G ent.'ra l Ca..... III 1,(lIllr.L\1 10 Ihl' small intes tim-, and il\(l(','( 1 to till' ,·Ilti((· !-t
,.It........ 1""__••' Site .. 1.lectI ,.n.wI.. '''lectI_ Ce_ _ tr.ti_
the P_k v •••• • Ud__I_ 1 00-_, 0.. .. PlAA fV&M
wcx:..o.N: CONCt N'~"" liO" (""'9/ 1(
1 46 120 1 18
Inle
Coudal lvrnbor ep;durol Brachial p1eXI.l$
007 053 0 •• 035
Suborachnoid Svtxutoneov~
"'_""'"c""""" 8e l'In-oo:d........ oIloxd~,;."g.., fllacl .... SC.-.k~.().Io.d 1Q84
'000 '"'9fl - .. 3 ......
w
~70-m
1'In-oo:d-.u<J~
EdOO
"""~ond C C
""':l
CHAPTEl! Q
127
(11lN ' IIf t1t,(' llllpOsilioll hy pml t'l,1~1i(' t·1l0'lllt·s ill til(' g'ol.<;tm illh"Stinal tra<:t, the-ir o ral all so rp tion h t·\trt ·lIw ly low ami errat ic. ~ l c )S t Hf tilt' Infonnanon on tlww kiml, of tl m /-,'S has 11Il'C'1l ohlailll'li fo ll(lwi ll~ lIOTI" lwu!ar pan-uterul ad minis trat ion. Fu r tlu' s.c., i.m., am! illtrapentoneul m utt's. d rug n-acln-s ti lt' s)~lt' m ic t:iR:lIlatioll I') ' Iwu mechanisms: d ifTlISioli thm uj,tll tilt' Inn- r-, tilial f1l1 itl, alltl ft·!It'stmticlIls ill till.' l illin ~ o f tll(' \':l-"l'1llar (';lpilb rit"S and by n lllH'(1in' How o f lilt' lnterstittalH u ids through lytll phat il' d.;Ullll'k ~ l oll'(1 Ittr si:l.t., is of p rim.u) · illlpo rt;\Ill" fo r p. t'Sll~t' acros s the capilla ry eudothcllum . l'olyp{'ptidt'Ji cf II's., than appru\i JlJa lt'l~· .)( 11 11 1 wmn1t' p rimaril y p,l'" th rt)ll~h lite ca pillar)' pathway, Those of ~n 'atc' r than allll ilit :2U,lMMI WIIllllt, un- h-ss ah lt, to trnverse tilt' edpi llary wall ; tl1t'Y p rimaril y 1'lItN tIlt' hh lll via tilt' I~lll phat ie path way. 1.~·mJlII IInw is slow ami {'aIlSl'SallSllf]ltion fm m nonvascular pa n-nte-rul sitt·s to l,mtinllC' for lIIallY hOllrs. a' shown in f ij,t, 9 ....'} for ~1~t.usyl ah.J recombiuaut lnnnan /-,rr;ultll (x.-'~ tt· n lil(:OJpha~t ' (Ulolly - sti lllu la l i ll~ f"(1o r (mok -cnlar wC'i~ht .. I S.£MM. to 3 -l,lMII) Wlnoll' ). Tilt' d nl~ 11;1' a half-lifl' of fl.!; m ill afh'r i.v. .uhninistrution, hilt f()lIo\\i n~ S. {' . ad ministrat ion. tIlt' plasma l11l1l't'nl ratioll is p mI Oll~t 'l l for at It'a, 1 42 hr . wi th a r ate of tLx 'lim' illdi{"ltin~ (ullt i lll l ill~ input. '1111" 1I0n \1Isc:llbr pa n-ute-rul m ule's "fT('r lilt' lId\'alll a~t' o f pm"'dill~ pmlnll~c'(l input fur short Ilalf-lift· peon-ius. Thu s. 1l'"1\11\C:11t lT part'lItt' roll udminlstrution allows fur Il"Ss frt.'l lut'nt ild rniuisl mlioll than tllC' L\'. routr- ...\ mai n (1111l1'01 Iwr't, relates to tllC' n 'p md ud hility IIf tlurt'1l'
o
6
12
18 24 Hours
30
36
42
t·ll(. ~'j , 1 1.'l'lIl~ 1......·" I. "Ii< "" " ( ¢:, (, ~L"~ I n·o, ,,,I';,,.lIl l In"'.....' l(r..."'J,"-' 1,·."....·..
'w...J:' ·nM"n~' .•Ii"'''L.t;nJ:
(...1". ti~J,,"i"J: j , .• • . ">li< IIi ,,,·>..,,.1 U ", t£.. ....,J .... IIi ,..·) I...ol". ill;',1i"" "f .oj IlWl< ~, n M' n~ults. lIhta.ic"..1in t'o'" ,1,tT"n'lll il.. lr.i.Io~J" ~l>1ry II... Lic,,",K'" ,,( II..· ,Ino~ f,>II<.... i lljt II " ....1<... tl( I....".ntt·r.d ;oo;1",inhlmlit..,. ..... L'I".~1 rnn" 1l' ''Jo:...,nl D , \I " rt.·" ,,·u, It T .. Sodlif" ',. s.. ",,,I Sio n. S ,I.: C\init,.l pll.olmUot.. l.i,..-1it· ~ 'Klit ... ,,( a ," " ",," Io...·"", ...id k J:n ",ll. (.K1" s, ( ;~ I ·CSF, t:" m. J. eli.. , h.w >t.. ~ :4.""""!:l. 1!:1!i".U
121
CHAPTHQ
('nslln' {'Unsbh' nl and mon- t'UTll p ll·te hina\'ai bhi l i l~' or Illil}' rt'fillin' til(" dl ·\l.·lopnlt'1I1 of 1II0 rt' SPl'1..1 fil' methods for ( Iel i\"t'ri ll~ t1wS(' dnl ~s to tilt' sil t" of act tou.
Absorption From Other Sites DOl ~S mav hI,' udministe n xl to vtrtnallv unv sih- of til(' bodv. Th is is cr-rtamlv trm- of local ;lIl l'stllt'lk~ . III rt'1.'t'1I1 years then- h'L'> ill"t·.; l'()IJsi
les s conwution al . .in-s, suc h 1t'> li lt' 11I1l ~. 11'('>:11 lOil\;I,.. ami bucca l (w .n i t)" ,t,> a IIw ans of ddi \'('rill~ dmj.,~ s) ""Slt·lllk-.i.lly. TIlt' IIt'W P(JI~"Pt·plidt· and pmt r-iu d m~s that an' poo rly mid (·rr.t.lkully abso rbed when ~h'(' 11 UrdU)' h,,\"(' r('('('i\"('t! parti cular .utent tou. Tr ausdr-rmul allpltcauon ha.. become popular for systemic dd i\l.·ry of small. ~(·Ilt ·I1lIl)' !ipoIlI.ilk'. pote llt molecules that n-qutrelcw Input rates 10 a(.'hie\"t' d Te(.1in ' tln-rupy. In all cases. considerarion hit.. to hl' ~H'II to the particular p roperties o f 11Il' sin- and rln- d m ~ . :'\OIlI.'t!I(']t'ss. IlnIactors i n fl uellcill~ abso rpuon fro m IheS(' sites art' li kd~· to ht' till.' same .t.. t!loS(' i n llllt'lll..'in~ ubsorptfon from tilt, oral, Lm., ami s.c. sites.
ABSORPTION FROM SOLIO OOSAGE fORMS formulation Ecpmlil)"of d m~ content (lot,S lint ~uar.lll lt't· {'flua lity u f dlk~I{·Y . TIll.' prt'S('IIt1.' u f diff i-n-nt excipients (iIlWt'tlit'llts in addition to t1 m~) alld lllimll fill1llri ll~ pmf,'l.'SM'S lIlay rt'snlt in dnsagt· forms l1mtaining rlu- S'Ul1l' dn S(' nf drug hl'1 m\i ll ~ difft' rt'lIlly i" t· it~J . 1I 1'1Il'l.' Ilnn-ason for It'slin~ for hioe quivu leuce of preparations of a d m~ iutended to bc' switd lilh!(' (p . 45 ). Gt'lll.'mlly, Iht' primary conce-rn is \\illl till.' extent of absorption . Ot:l ot<;ionally, variations ill ah stl'l'ticlll mit' may h{' impo rta nt. vtucb ofh-n depe-nds 0 11 thr- dl'~rt'(' of uccumulatlou that O( '(1 Irs un multi ple t1n<;ing (F ig. i--6. p. lSi). 111t' major (·;lIISI.' of dilTl.' rt'IK'('s in abso rp tion o f a t lm~ from various products is
Dissolution 11ll' ff.'
Di ~5f)/ution
n'al izill~
Ihal ahsorption
Entry into
... body
T\\1J siluations 1m ' IInw (1msidt·n'l.l. T Ill.' first. tlt'pit1ed in ri ~. 9--6A. is 0111,' in whid l dis-
(HAP1H
129
Q
so lutioll is a llllldl faster p nll't"SS than is t'llIT)' o f drug into the hotly. Ct mSt"(llIt·ntly. mos t of tilt" t1 m~ is di ssoln'1l la-fon- all appn'dahlt' amount is ab"orht'tl. 1It"n", pe-rnu-ability rather th an dissolution rate-lunus absorption. An ccunpk- is rlu- ga.s tmin!t'stinal a bs orption of IIt'tlrnyt'in ¢\"t'll ax a ta h!t.,l. 111is jXJlar .m lih iolic tlissol n.·s rapidly hUI ha.s dim<:ulty P"!" t·tl":ltill~ tlu- ~,ts tmi lllt' ''l i nal t'pi tlll.' lill lll . So. liult· is absorbed. Difference s in rates of dissolutiou of lll.·u lII~~·ill [rom (Iillt'n 'nt tllblt·t" ha\'t' little or llo l·llt'1:"'l 0 11 tlu- spt't'tl of absorptinn of this t1 m ~ . In tlu- second and much mon- <1I111l11011 situutiou, shown ill Fi~. 9--6B. tliS.SlJ! utiol\ pml't'l.'tls rt·latiwly "low ly', '!lld an y (lisso ln'1! d m~ rt'ild ily traverses tilt' ~a.stmin lt·slillalt·p itllt' hmn. ,' ''sorp tion cannot proo-ed ,IllY faster. howeve r. than the rate at whi<;h ti lt' d m !!: tlissn ln ·s. l1li\t is, absorplion is d is<;o lll!ion rate-limited. III this cast', dm ll~t"S ill dissolution profoundlyaff ect Ihe rail' . anti sometimes lilt' exten t. o f t1m~ absorption. Evidence sup port i ll ~ dissolution ratt·· limilt'l.l absorption cumes fmm the Ilntit't'a hly s It""'t·r ahsOlvtion of mosl t1 m ~s from so litl t1os
Factors (ontromng Dissolvtion \l allY factors inllllt·nl't· Ihl' dissolution of a dr ug. AlIlon ~ the se an' surface are-a. solubility. pl l. .uu l s t i r ri n ~ . Ex palll. l in ~ the- SIln. Il"t· t'xjlC lSt'1l to IllXly fluid s hastens t1iSStllulioll . Ht't l ll lil\~ Iht· sin ' o f tln- solid p.,rtid t·s is 11ll.' Illost conunnu uu-aus of ach i{'\in~ this ~l.lal. To this l' lTt'l1, for t·...muplt· , man-rials ( di " i n lt '~ra n t " ) art' tncorporan-d into tablet s thut {·aIlSt· tln-m to SWl.' lI IltlClll cont.u-t with watr-r an d 11ll.'1I 10 di sint l.'g mlt· into gnmulcs that finally tI{'a~rt-galt' inlo tilt' tIIiJ.,rillal [itn- d m ~ partick-s. III t1isso llltiull filtt·-lilllilt't i absllI-plillll, tlu- concentration of t1 nl~ ill solution at thr- abo s orpttou silt- Is h' pt low ht'1·.IU<;t· t1i <;so t\'l.'t1 dm~ mpidly enters Iln- IMllly. Tln- dri\ ill ~ fort't· for t1i"Slllutioll is tli rt'l"'l ly n-latr-d to the Stlillhilily of the dnl~ at the surface o f till' disSt)hill~
A. Permeability Rate-limited Absorption
100
B. DiSSOlution Bate-limited Absorption
Absorbed Drug Drug in Solution
100
Absorbed /
"-
Solid Drug
Drug "
50
_ Solid Drug
o
1
2
./ Drug in Solution
2
3
4
t·iK. 9-6. \\ 1"'11 ..1"" '1" " ,11 i> 1"·n,,,·..l ,ih ~ r..tt··!i"' i",t1 (c • ,\ ). "....I " f tI..· t1m~ I"" . ..1(ml,," ..110,..·) I..·r,,"" "" .'1'1... ..;.." ..• fr...1i"l1 h I....·" .."."..t.... !. In t....,tr t . ",I..." tl.,... .t..li"" nl lt·· !im ih ;d"" rptio" l ((::.-. ii i, '-"r;. Iilll.· ,tml( i> in ....Iuti,.., ( n..1li"d .tI II..· "h''''l'tic." , il.· '" ..,,~- Ii"..·: ,I",,, i. ;d""..t"..1... "'" ;0.' il .Ii .", .t,, ~_ X..'i..· thai Ih. · "'..~ ,ri ~ .. r ,1 m:.: n.. ..1... >rI"...1 i. aho.ll~" r'''llltllll till" r.d... linllti"l: .It"!" in ...,Iutio.., in C,,-,,· .'\ ;11,,1... a ...,h,lm Ca....· H.
130
solid. T his explai ns why tablets. capsules. ,lIltl even sus pen sions of sll;l ri ll~ly soluhle dnl ~s an' prOlIl' to absorption problems. E\"('II if dissolutiou WN t' 1I0! tln- rate.lilllililll?; ste p and s,;ltu ralt't l solnnon at til(' abso rp tion silt' l:ou ld Ix· llI,u lllaillt'
it
"t'
Gastric Emptying and Inttsta Transit Befo n - di S('II.ssillg the nlll' of ga.s lril· 1'lIlpt~i ll g Oil ah s0'1)tion o f d nl gs ¢ \'t' ll us solids, couFi~. 9- i . Slll)',\tJ
sider til(-' iufonnalillll pn )',i dl'tl in
AB5OIIPTION
CHAl'YH Q
131
I n routruxt tUl'q 'lIh ill Ilw stomach. I ll(' transit unu- uf sol i t l~ " it hint lll' small inh'sl i l\('
va ries liu ll ' among: sllhjt'{1s, appears 10 1)(' Independent of either tilt' sin' of a su lid or till' pn'St'Hl't' o f fotltl in t ill' slt ll ll ad i . ,UIJ is n 'lllark;tllly slUII1, app m 'dlllatd )' .1 11r ( F iK 0.--7), a tiuu- sim ilar to Ihat foun d fo r till' truusit o f liquids. Bo tll solids andhqeids app<>;lr to rnovc down till' small iuh'slilll' ;tS a p lll~ wi th n-1;tli n ,ly li lt ll' Illi.\i ll ~. As the mouth-to- anus transit tiUll' h t~vka lly 1 to 2 days. Ihl'S(' llala 0 11 ~,t~ lri l' and small tntesnnal tra nsit ti llll~ indkllh' that. for tln- majority of this tiuu-. unabsorbcdmatr-nuls an - ineither tht' large Iltl\\'t'l ur n-cnuu . I'rm i dl '(l with till' ph)'siolt~l' illfu nnation above-, IllI" pos sihle mil' u f g;lSt ri<' ('1111>~irl g: an d inn-stiual traus it on tlu- absorpuon of drugs gwen ill so lid dOS
It • • •
Stomach
Smalllntestine
II 10
••
8
I
• •
0
•
-c-
Eo 6
•
~
E
;=
." ~
"
• • •
••
4
~
2
o
•
•
-
~O .. I Fasted
Fi". lJ- 7.
F. ~~ 1.
D Q...• •
•
I
••
}.
••
lIyP
•
...
•
• •• • •
•
•
•
•
Q •6 ~ •
•
• •
• • ••
J
••
•
t
••
Ught Breakfast
,""rtlt"brJ:.' a I...a,~
Heavy Breakfast
Fasted
Light Breakfast
,,,,,ai, i 'lt-n''''''~ lilt· ):",-,Irk>Irall" ll1 ml' "I' .",allp.·lld' (I,Lw."
....,." "",n' "... ti..... Uy. " r laru.· ,i"ltl.· n"ih (" ,,,,,,...1ri"·l.~ ). In co"lr...,I. ,,,'ill,,·, " ,1,,1"rr.'(1' Ih.· ,,"all i"h·, li,,,· t, all. i1Ii " ..·, 11,,· .1.0.1.. (l",L"kl"aI po >l nl•. I,t... :!:.
• • • • • ••• ••
S E.. i" . tic·.d. , 1 10:- tlK' .....1a"I: .1 .. , ....
, ~>l;<j, .. ...1 ill '"·,,lt h~· ~," nlf
r. ~
••
• • .\ • •
0III• •• •
••• •• •
• Heavy Breakfast rin·..~ ) alld .
.. 1,,,,, II..· pI1~,in" .i'.·..( II..·
" I' ... ...", ...1n n·"~. al .. 1tI..'i, "" 'a" . 1,,1,. ". i"l: .In'I:'(''''' ", " KI"i" h1U"tinlt
"t.>h·riak Th' p"in" will, " n ..m · i,,,lil·..h· tiK' .. IIi
, I,,· till '" ~ i'KI;'"I<... 1. (A,Ll'h ...1r.....", 1);1' 1<. S.S..
132
c-wttec
icdliu G art' mp idly I l~llrul~·/,{'(1 to illadi\1.' Jlr( lt llld ~ i ll tilt' addie envt ronment of thr- stom ach. Salil) 1k add is a ~ilst ril' irri tant. A so lution to hoth f)pt·s of pr olih-ms h iLs Ilt'('11 to (,11,,11 these- dm ~s \\; 111 it material n -sistunt to add hul 110 1 In tilt" intestinal Ihuds. ~ lallY slI(..1I enteric- coated products an' la~(' s i ll~l(' tablets. ami tilt' tillie' taken for an illi ad tabk-t tel ll'. slid , r-un-ric-coated product s an' lIlIt til II(' 1ISl.'(! \\'11("11 a rapid am l n-habh- rate of abso rp tion is required. A p n l(Inl1 {'u lllp'JSt'tlof ('nle!ie-l u illt'(l ~m ll ll l('S is an impmn.·llwllt lx-cause tilt' run- o f d e!in.·ry of the grauuk-s 10 III(' int est ine is t'Xjlt'l1t'1l 10 Ix' mo n - n ·lialllt·. I lt' i n~ h-ss t1qx ·mle·nl em a s i n~lt ' e-vent am i o n food. P(MJr D isso)uti o n. SOliI(' d Ol~S , such as tilt' oral an tifun J.:al aK('nl J.:riS('oful\in, an- sp'lrin ~ly soluble in both ~,l"l rit- and Iute-sttnul Hukls. \\l len 111('5(' t1m ~s an' adminislt'n'1l us a sohd. the re llIay aln'ady ht' insufficient limp for compk-te d issolutioll am i 'I h~ lrpt i(l l\ . wtth a fiwd short tilll(' within tlu- sma ll intes tin e. n-teution in the' slo mae h inen ',l'i('S the tillw for dnl~ 10 di s....l)"'· h('fo rt' (,llh'rillJ.: tln- iutestnu-, tlu ' n'hy fa\uring inert',l'i('(1hio;w aibbilily. As !lU'lltiHl\('11. fOCI(I, and fat ill pa rtk-ular , delays ~;lsl ri(' Plll pl~i n~. Th is dday Illily lit· 011(' of tln- explanations for 111(' ohS(,rYt'1l im 'rt'ilS(' in tln- hiua\'aibhilily o f ~ris('ofllhi n whcu tuken wit h a fatty meal o r \\;111 fats. Sub s("fjll('lItly, us tilt" inh 'stin al fluid and contents 1ll0\t' inlo tilt" largt' tnte sttue am i \\111('1' is reabsorb ed, tll(· noslllt ill~ I1lmll;.cd ion o f Ihl" so lid content s lIlay S('\"('rt'ly limit fu rthe r di sso lution ami ht'Ill'(' abso rpl ioll of d mg. Co n ln)lIed. Release Produc ts. nit' conclusions d rawn for sll;.lringly soluhlr- d m~" ma~' also apply Itl certain ('(mlmllt'1l-n'lt'ilst, do sal?:(' fon ns. Scum- of tln-se an' tUiltt'(l "'ilk or contamed .... tt htn. a Il ondi sinh~rdtill~ material throug h w!lid l the n-h-ase r an- of d m g is indt,pt'nl1t'n t o f IMlih I' ll and a~t'l lioll . In Slid . ( " (.\("S. V;.lslri(· t'lll pl~i nl?: hax litt l(· (,!T('11 011 tilt" rate o f drug ahso rp tion . Evt-n t!loul?:h tln- solid dosal?:c' form Illay lx- rt'la illC'(l ill til(' stomuc h, til(" n ·I(·;lst'1 l drtl ~ is (,(JIltinuuusly PlJlpl i('11 with Ill(' g' lstri<.· fluid into lilt' dU(I(I(·nUIIl mid i~ il\'uilahl(· fur allSl'''ltiuli . Any c1c·l.l}' ill the- ,l.!;itstri<.· t'lIlJl t~i lll?: of slld l p r oduct s p rnloll~s 11\l' totu l period for d rtlg n-leuse and absorption . For n ';lsoIlS diso:'uss('11 alxl\"t', this dda~' is mo st likc'ly 10 1)(' SI.'1'1I " ; Ih I,I')!;(' singl(· un tts takeu Oil ;l f('11st(lIllilt'!l. It \\lIUld lit, IIIm;St·. hnwt,\"(·r. to dl·!lt'llll too 11lI1l'h oni llis do:ola)' lo .lellie\"(· a pm lolll?:l'(l ahsurplioll profil(' gin 'n tilt' wo:oll· "·ll(l\\1l unp n '1lit'lahilil)' o f !l;.ltienls' ('atill~ hahits ami tl wir ~t'l lC'ml la(·k of tUllip lillll<',,(' ill ta";ng 1ll('(Iit'a lions. fll rtlll'nlluro:' , su mt' <'llll('('m m ll.sl t'xisl Ihal ll llll1l;.t<.1ion in Ih(' la~t· intt'stinl' may pro:·dude rt'!iahll' input of d m~ 1"lt'YOlltl I2 10 16 hr. T his wOlllcl S(·\'t·rdy limit tilt" dt'si~ l of <',(lIllm llt'1l· rdeil'i(' do s;lge for ms o f d m ).,"'S \\ilh sho rt ha lf· Iiw s inlt'm)('11for oll("('.a.day ad minislr:l!io ll, Th at said , dala fo r SOUlt" d mg·dd i\"(·I)" sysh' llls indit1lh' th ai rt·liahl(· 1Iml slI_staillt'(l ahsUll ltioll for lip to 22 hr <'1111 1M' a('h i('\"('(I. Fuluro:' \\llrk in Ihis an 'u is 1ll'1'(!c'(l to IIllclerlitam llhe S(,(lJX' aJl(l limilaticlIls o f th(· appm..cd, . Om' lim itation m n lit, thc' pmpt,rtit's of Ih(' drtl g itM'l f, ,lS 1I0W dist'lIsS('1I.
Ganging Rate Control
n it' mit' of abso rp tion is ('C llitm lll,(! by a dc·li\"(·ry dt '\i et · RS I OIl~ llS rd t',l\(' fm lll Ill(' c1e'\i l't· is tilt' mh'.limiting shop in ti ll" ahsu rp tiull pn )(.'('ss, \ Vilh till' I' . SA Ie I'm fCl r drtl ~s d("t.·n·ilsi n~ alm lR tilt" l e'll ~ h o f t!w in lesti nal tm<.1 . Ihe mle limit ution ('(mid dlanl?:(' fmlll tilt' 11(,\;<.1' to th t· inttoslinallll("mhmll e ,l" Ihe dt'\ i e(' IIlO\"('S0:10\\11Ih(· inlt'slilw ( Fi~. 9-H ). \ Ind l o:IqM'Il(Ls 011 Ihl' n·latiH' impt'1hlll(,\-s for dm~ lllll\"('llleuf ill lilt' dl'\;('\' and ill ti lt" intt'st ina l \\1111. III tIlt' slllall inh·stil\('. p . SA is at its h i ~I ll'sl ilnd ('olltrtll may t1lt'1l wdl lie \\; Ih Ill(' dc,l in-ry dc'\ict·. 110\\"(,\·t'r. O il 1lI0\"l'llIt'nt into Ill(' ('(11011, J' . So\ lIlay
133
may Ill.' a problem. En -II wi th rapkl-rt-h-ase dOSllj,:l" Forms. ah sorption of tllt'st, compounds is !'''' 'nt ially n 's tridt"tl to t i lt ' small in lt' slillt' (t·.g.• Fig. 9--1 ). Cum-nrly. IIUWt>\"N . it is difficult to make any quunt itativr - pn-dict iou of tlmst· dnl ~ fur which coutmlled d mg rk-lin 'I')' run hI' adli,'vl"t1 I )( '~und li lt' small inh'stilw . Rut dea rly. wln-m-u-r n ']l'lN' of t1mg 1)(')1111\ 1 t he stomach ('onti lllll'S for 4 hr or ilion', some of th e d m g is likt'ly to he TI'II',l'it'11 i ll tlu- Ia~(· iu!t'sti rw ( F ig. U- 7 ), Mon- needs to he k 1lU\\11 abo ut the rdation sh ip h d W t ' t' 1i tilt' pllysit( ldll'lIl it',,1 pnlpNtit·s of a mok-cuk- and Intestinal pe r nwalnfuy. C urrently. tilt' Ollly "'('OliN' is 10 ('\"a lualt· Ilw dm g tlt·lin -r)' s-yslt'l1I ill r ;I:(J.
A
j_
0.8
a'" ~
~
~ a.
iii
8 0.6
c
04
!i.
aw &
o
0.2
o
L-----+--=:::====...::::: o 12
6
18
24
Hours Fi ~. 9--1\.
TI,,· rall' nf 4h"'''l'linll " 'Ldino In 11K· ral,· of \~ "" I;",t n·It~.... ., fmm .IIl nr.ol 24-lor ~"~I;u,,,..I ·n·"·a...· i" · , 1I, Ii " ,,· .... ~ ..·n u..",·"..." l ... ·n.... 1I" . uM'ml.r. .".. Il f 11M· ~q n>i"Io~ill;tltr....1 . noll,,·, Ih.m n·I,·a-'.o'. I ~"", ... ral,' li ""linl:. TI,,· d,an)(,' i " ral,· \~",In~ fnm, n·.......... 10 ""·,,,hr..,... '''-'n,n fnr IIJm)(" ill. " "'hr..'..· I..·' '' ..·..hi hl~" TI..· r.II., "",In.l i"'I..", ,,,1 loy I"·n,,, "ilil~'l. " "1 in II..· (~II (6 1,r i. , I " ..' II,,· hIt '"~ fltT Ih.· , ",,'i<~' In It,,,,,· 111,· 'I''''''.. ~, a,.. 1 Ira,,";l tI,,· . "...11 i"I, hfM·. ,k.ho..l \. ·rti<...t Ii,,,·) I ... 1"·m..." I,,hly " m"d, I<"" 'r Ihan tI' 41 III II..• ~",al l 1n" .. I""·. TI,,· Sl" "'L
,10·1;" '1)' '
",ri," . .
"M'
d.~,;tll
'Ii " ,1.,;<."..1f l'l"'''l-:o ' nf dm i( ,;tit· ..
•
R Kalo' .. f n ·...,....
in 1"""' 11
~....:.~o\ \ '<1
... _ 1< ' .0\,.
Roll' nf ah•.,rpti<>u
....1,,·1'· .-\" i\ a" ..",,,1nf 1'·1.-;<." ..1tin ,!!: " ...ir I.... ' ....Tl·a.... ill p . .\0\1\'" will, tnr..•. A. lit(' ...111,,1 dl" n~. ·. iu r. s.\. .1.,,,1 \ '" willt ti ",.. an ' unk",,,,,,,, an ... p' .... ·nlilJ (h..aI f·lif,· " f3 1,r) ,"·d i,,,· ill lI"·'''''''I''''il.· i. " " .. I. TI,,· f"I.....,,,1: '..".. IiI;..... an' ~; " "' Ltl ' .." A. r · s.o\I\'" i•• "m':;'·"l!).' I.ito:i, ("1'1,,, _ 01,,.. "'J III ,."."... tI..d lilt" r""'-(''' 'ln.l li ,,~ .lol' i. alw"~,, in 1I ,Io"'i<~' ",11, ,al.· of ah.. 'rpti"" makhin~ rat.. of n'''~''''''' . R. p • •0;.0\1\'" b IUlor - ' . a \ ..1,,,, fnr .... I.kl , dnlll: ;~ ;o.1"'.rI 1virtllally.., ' I"i<-kl~ .., it is " ·It ~ 1 .. ~,i ..· ill lI"· I"" lil1..J sll",11 iUIo-M i,t<' 1>"1 ,,,,, ..., f" " I"'r ' ~"'1' 11.,· l("'l ruil1l lilwl lr...1 ....f,, ·n· nth' (. " ,1" .1 I" ,tI Jo.... k ..· I. 1.. , 1. C . p . S.o\I\·" is II,r - ' . TI..· r41.· , of ,,1"""111;'''' ' ...... ·r lIull'l II..· ral,· .. f n'It·....•. Thel'nlllll':1 fail. In (..,In ,j a1""'1J1itIlL D. r · s.o\I\'Q _ n.1 I,r- I. I\;'h - ",,,' n.l !i, ~ al" .." , "nlin*,' "'tl. II..• Il..·mhr '.... of tI... t.... ln linl... hna! 1""'1 III .011 lim..... In ,-a,,'" Il ,,, I). ,Inl\: ",.. " ""lal in II... I"" n ..f 11M· ;n l,'\I i", The Iln'1l "",It'r .."..I, C'l '''''''' n·L,I" ... t" II,,· Iln~'" '''I< It'r li lt· n·I.·..,,· mr... (' " , . i. tI,,· fr :t ;'m ..f ,In,s:thaI i~ IlI",>ri"..!
".",_..1
' 34
CHAPT[ i Q
Precipitation and Redinol,tio. Absorption is llo n nally l11Illptd (' within I Of 2 h r u f i.llI. or s.c. uduuuistrunnn of au ' U l lll "iJ II.S s olution of a d m ~. Then- an- {·u1· pfiollS. il \ S1't'1l wi th p rutr-iu d m j..ts ( Fi ~. 9-.5) alld when ill~"(..t illg a solutton uf a ~t1t of (' i tl lt' f a spariugly snillbll' add ur ha.'O(', For t·\l.lI nplt" illt lluugh. d llortli,\7.('lxlxidt· hydrochloride. in sohr tion , is {'wlltually (,(Illlplt·tt'ly ahso rlx'(l. ubso rpnon is slnw from til(" l.m. sin-. II llwl'\l·r. largt· do st·s somennu-s appc'ilr til Ix' ponrly (·ITt"(1i\l' or im,ITt"<.1h"t,. Indeed. ahsmp lion is I"\"{'II slosH'r limn Irom ,hI' gastmin lt·sti nill tnIl1 . when {·a psll)t·s of d llllrtli'l7.q )oxitll' h)l ln)(.'lJIoridt· a n - adnnmsn-n-d (Fig. H- Oj, TI lt' cxplauatton involves cousldr-mnonof pi I, snlubilitY. lwrfusioll, of a bsorp tio n IJ(J\\' he{'tllll es lim ilt't l by di sSlJllItiem of Il.t· p n.'t·ipilah'tl d m g. IIIIw('W I'. till' sllla ll surface un-a. IfJ\\' so luhilit)'. limited perfu sion. am l m inim al sti rri ng n-ml 10 keep tln- ra il' o f tlis.'iulut ioll deJ\\ll . The result is p m t ral1:I't! ah Slllll lioll 11\'1 '1' mall)' h01l1'5 or even days . In contrast, «leorpuon follfJ\\i ng ural ad mi ni'itra tioll is rt·la!i\l·ly rap id . For reas ons aln ·ad y d ilit.·lIsSt, I. a ",rrt'a h' r t1t'gn 't' of a",rilalioll, a (,lrl-:t'r volunn- of fluid at tlu- site, am i a hil{llt'T nih' ofhluot l ll' l\\' til tilt' Wlsl nl inh 'sti nal lrad pnllno h ' uu m - rapid t1isSlllution uud ahSllrp lioll fulleJ\\i ng ingl'slio n of d llnrtli,v.(·j'ltlsitll· "~'ti mf:l l le lrid(· . AIIIlll ll'f (·sa mple is diazepam . a dnl ~ tlrat is spe r mgly soluble a nd slowly ah smhl 'tl when injl't'!I't! lnt ramust'ulady. 111is t'sSt'nlially m-utra] d m ~ is kept ill Slliulioll wi th lilt' ait! of Pnlpyll·l\t· glyt, ,1. Precipitation at tilt' injt't.1:ion site 1)('{'l11'5 wtth Ililutiun a m i abSlI'lltiun of t his wa l(·f -Illilit.ihlt· solve nt .
nl(. 9-9. A
cO--OJ. ....
I~Ml fn MII II,,·
.,1...
;nlr..mU'I' lla,
"; 1.·
2
1to "~M'U
, al",1f]'"
Ihan {min III<'
nr..J O n I"llh ,K'("lI.. kM.. ,'Sl l 1tIf( " f t"'t.mh. v l, ,,ni<.1.. h~,l n "..,t.IritIo· "...,.. ;lOh";n;",,,",,1( I niWl . - ,1.3 1i ~U. I R...lr.....ll fnlln <:", ·nt.latl.
.~
1lJ-. SI~Io" . R I.. ;u,,1 t;"d " W,'M" , J.: s t.....-..h·
d ,t.onli""'1"».ltIo-, :,,_ En!:!.). M,..1.. 291 : 1 1 1 A- l l l~.1 9j-l H'1Irinl...1
"'fl>l kM. .. f ;1>11";1.111"'1<."1.... 1~·I"'nni ..i"".)
o
•
o
• 40
20 Hours
60
STUD YPROBllMS (Answers to Study Prob lems ore in Appendix II.) I.
List
OIl It ";lSI
three reasons for rt'tlul't"tlo ral bio'l\'uilahility of a d m~.
2. 11\{1il'a lt· tjn- ilel't1r.1t, · o f til(' fullo",i ll~ state ments: a. \ \ 'ln-n ati mi nislt ' rt'(l o rally ill so lu tio n. Wlslrit> ('lIlp l)in ~ mW-Jjlllils th e absorptiou of
srnall lil)lJpllilil' t1m~'S . h. Fur rapidly t1hsoh;ll ~ pr oducts of a d m g. llifTl'rt'1lt't.'5 in rates nf d issointioll lllarkt'tlly afTI'd tln- p h sm
,1.
.t. S. 6.
sleJl.
c. Polar d rugs an.' p rilll ari l~' ahsorlwtl Imm tilt' small intt'stin(' via lIlt' rranse-llnlar route. d . A substantial Fract ion o f hio<\\';.tilab!e dnlg enters the syslt' l1lit: d rt.'\ltltioll via tlulymphatic m lllt' for Iargt· ( ~ I , \\'. ~rt'iltt'r than 100,000 WllIole> protein d mw; admlnistl'rt 't l lntranu rscularlv. I ' , Lo u ).:t· lIt1l1disilltl').:rati;lg coutrolled-n-lc ase dosa~e fo rms ('IlIllllu nly n-maln ill tilt' stomach for 6 hr wlu-n takt'll ju st ufh-r a Iwit\) , 1Il('i\1. U st six
,.1t'.9-5. 1'tQl'f 11l'Y
ce
""" •
C~ "C If I1lS"C
oYoIe<:ulo ' _g~ r
Ig/molel
pI(o
PoIa"j, 01 UIl1Qflil ed form SoIub< 'Iy 01 UIl1Ol'\'l ed !OIm Img/U
327 8'
[Acid) Nee polo,
13
eeoc
• 273
78
(Aminel Neepolo,
ceco C
315 _0'
ooo o 378 Oucle
coepcced
Pd,,,
ISO
(;in'n tlla! rlu- conven tional sing!l' doS(' uf hoth Dm g A and D m ~ H is IOn 1lI~ and thai IM Il h drugs an' slah l" ill 11U' gastromtesnn al fluids. circle the IIImt appropriate tim ).:, wo rd . or phr.l'it' (in Italtes ] that completes the foll'J\\i n~ statements. a. The su d ium salt of Dmg A di sso h't's milch [aster. milch slow er, (It rs.~'" ti(llJy thl' n il//(' m t" , in a so lution o f p ll 3.0 tha n (as) dot's tilt' fn." add ill a solution of p H ,'j .U. (O the r factors, such ax surfal" an'a and su mng. an- tln- same.] h. Tln- I.ytln x:hlorid(' ~1 1t of Drug 8 should d issolve muc1. fint..r, milch ., Ioflx ", (It ,'_"w'lItitllly the .wH/1I' mt,'. in the stomach of a patient with acblorhydrie [uo ~ll'it riC illid ~"l,rt,t ioll ) than ( il~) in it pa li('nt \\i th normal ~a.~tri l' funct ion. c. I)m~ A is poo rly absorbed wln-n taken orally as the fn -e add \,illl lUI) mL o f water. 111t' hioa\"ai lahit i~' of thi s drug should 1M.' siK'lifieantly incn ·il'K.,1 hy taki n~ tilt' dmg Id O. 2(XJ ml. of untrr. in diddn l llm rs dllrill~ the ,Iay , on an empty .~tomllc!" d. Abso rp lioll pr oldcn» an' Ii kt'I~' to be grea ter witli [)m~ A. B , whe n adm inislt'n"l:j intr.ullust.11Iitrly il'i un a{IU("l:)us solution of the .~f)di lml, " yd mclllmide salt. r. In T nbh- 9-6 1It,Iow art, !islt.,! tIlt' Aue ,·alm's of dpmRoxadll, a d m g \\itll a hm:atl ill\timil' m hial al1i\ity, foJloy,ing its ddh"l'lJ' ( 100 mg) in solution to vari OliS region s o f
CHAPTf &Q
136
the
~~ l'f nJi ll h-,;fi nill l m(·I . Cipru flu Xild ll
aplll'ars In ht· stahle.' i n all (lOlrt !'i of thl" ~,l-, lm
inte-stinal t ract . , ..... 9-6. AU(' Vl;Iluel of CiproRoJlacin after Delivery of 180 "'9 to Va rio... Regions of the Gash'otnte.tinal Tract'"
1 48
AUC(mg-{/h'l ~A,booooc 1Od. "",
_
_ ~,
f ";' ,
~ _ *- ~
v, "",-,--,, 0
9
03 8 _
s-b, "H
0 2.4 008 cop<;lb.o:.. ~ ... dIIoo.to~ cJ"
0 ,05 ......,.., ~ OQCI
JO))-30 IQQO
a. From w!Jit..h silt' of the ~ll' l mi ll t t's li na' trac-t, stomach, smal l ililt -stint', o r large.· in tesnne is lilt' Illajo rit) ' o f lipmlluxatin likely 10 Ill' ubsorht'< l follu\\ill~ o m) udmin -
tstrauon of t ilt" d m~? h . Bil-"t'
DISTRIBUTION
OBJECTIVES The leader w ill be able to: 1 Define the Ioibw ing lefm~ : a Perfusion limilork>n in dish'iburion b . Permeability limilolion in distributiOn
c . Ifssoe-obood equilibl'ium distribution ratio d Fraction unbound e Pbsmo pt'OIein binding
2 Deenmre lhe plasma co-ceenonoo. the a mount 01 drug in the body. and the o~fenl volume of dislTibvrion when any I'wo 01 these volU8$ ole known. 3 . Describe the efIecl3 01 perfUSion lim'lOtion. pe!"meobility limitation, and the li~ equilibrium distribution Iorio on the lime required 101' dr ug dislribulion 10 the nssoes. 4 . k.certoin whelhef , /Of a given omounl 01 drug in the body, the unbound plasmacoocenno lion is lilety 10 be sensitive to vorialoon in pcseo prolei n binding when the volume of dislfibulion is known ,
5 . Cokokne the fraction of drug in the body rho! is:
a unbound b In the eXlroceilulor flUids c. outside the e erocellokn fkJids d bound to plasma proteins e bocod to plasma proleins in the eKlroceilubr fluids I. bound inlfocellulorly (in Of on tissue cellsl from knowledge 01 the volume 01 disrrib"riOn a nd the fraction unbound in plmmo 6 . Anl'cipole!he effOCl 01 cseed pkwno prOlein binding on the half-life 01 0 dn.'9, bccod 10 albumin and with a volume 01 di$lliburion leu Ihon 0.2 l/kg
fJj ,U1/JIIlj"ll rd; 'r; 10 tlu- n ·\l·r,ihl, ·I r.ill,f, ·r of dOll!: from OIW location 10 unotln-r \d lhill l ilt' I... ... I~ . Dl'fillilin ' illllJrlrlalioll 011 l ilt' c1i' lrilllllioll of a dOll!: n-qmn- i" I1IC ' ,~'lln'lIl"1l1 ill vartou-, li"lI' ·' . Slieh c1"la 11,1\\' 1"''1'11 "hlaillt'(! in animals. hill an' .·' ...-ut inllv bd,inl!; ill huruauv. \ Iud l uv -ful information Oil rail ' alll lc"1l'1l1 of di ,trihulion in 111111'1 ,111 ' can l xde'rill 'd . 1I0 \\I 'Q ·r . from oIN'I"\'"lion' ill hle... )(1 or pla, ma. 'I11i, ('hapl('r l"plon', t1i,l rihlllioll and its applil'al iuu , ill dirlkal plla rllla("okindil.... It hl'~in , \\1111 kim·lit· u lll,i d,·r. lliollS ;1m! c'lId, \\ill. I'e!"ilihrillll i 1'(1111'('1''''
RATE Of DISTRIBUTION Di, t rihlllioll of tlnlg, te l anti From blood .uu l otlu-r tissm" "{'('urs al \ a rium mil's am ! to \'ariOIl' c·,Io-I1". S('\t'ral fador' dl'll'rllli ,w l ilt' d i'trihlliioll IMI Il'm of a dOlI!; \\1111 tiuu-. 137
CHAPIU 10
131
IlIdlll ll'(l an- 1I1·lin ·l} of d Ol ~ tn th \Ii('S by hlo od, ability to ('ross tis-an- uu-mb ram-s. hi lldi ll~ \\11I1i ll hlood am i tissur-s. alJ(l l );'trtil ioll i ll~ Iuto fat. T issue uptake, 11l1ll1llo nJ,.. <''11Ilt",1 extra!"tHtl tjOIl . 11 1l1lilllU'S towurd equilibrium of li lt , d iITusihll' (lin n hl."tw ( '('11 ttssuc ilml h lllOc:l l"lI;' rfll ,i ll ~ it.
Perfusion Limitation Di!ol rihuti ou . likt· ahsorp tio n ( ~'f.' C hap. 9 ), ca n l)t· mtt·-limilt'(l hy dtllt'r Iwrfusiou o r 1)('1'Ilw
om 7 '0
70-k. M_ _-
700 200 200 >'00
"
350
05
,~,,""r""" ~.....
.
,.
II
~ <
't
h"-1. l<JB
0 ,03 0 .6
300
6
77 50
,....,.
J.
08
"":6
15
...-j().... . , .
•
22
10
0 .025 0 .""
'5
0' 2.
I
100
500') l~,t~,.I",""J<:
4
750
'00
..,
0 .5
15=
OO}
0 .02
5
1.:
,'00
" 03
.. I
, H)Q
050 13001
i 71Gvlj
I2
02
25 15COJr 250
20 20 0"
'6 43
0Pw-"
1"'",. SI_ .. D
..... T1_. u__ .._I c..MlIltI_ I
·"ldF'>"""",.~"."~<",,,_
, .... j
.....
'
....
0 .071 ?~,
~,.,""...._ ,
:;
....-
d.>- ""',...-_
Of'd--. ~ ~'" 101093-1095.1 QllJ Qtp• • \I _~ , _ ~ Of'd """"'..". Qt. net "'Cl..dod ' h:ldoo "" ...... ~ "'1P'"
ox-
Bit, 10- 1.
l>OIIo: i. po ·..I....1 In .. Ii-.".· ..I ..to .. r-
IN l.o.I "'...1 t~ .. ln ·"'r.cl " ,,{ <.'., ..... 1.., .. ...." . ....I" ..t In III<' rn"t"'1 "r I,Ie..I II" Q. ,",,,.1 C A _ TI l<' .1011( Ie·..." .. Ih, ' I" " M· ..I .. \1·' M '~M" ..."lr..h"tl o( C" ..,,,I " I .. r..h· ' ~ I ' '''' In V ' C,., TI l<' II• • ,..• '~ ""..."Ir..ho n , C r,
i'K"'·........ .. I..·"
rdl" "( 1'0....·111;'1" ... ru~ ...... I, r..,,·
,,(Ie·;o>; ,,1o: ill ,I..• w ,,,.,,. I.Ie ..I, "'KI IIK' '~"''''"''' , TI K' .."".. " ,1 ill ,1M' h u,... i. tI" 'l'n >t hK1 II{ \ .r . , ,,, . .. ~ " ''''.
"r II I<' h.."w. alKI III<' 1i' ''M' tlml: ,~ ..>t"'·lIl....l itlll _
a (0:::::::::l (C A
\
Tissue V,. C,
\ a (C,
)
(
"9
CHAPTER 10
FiWlrt" 10- 1 shows 111011(1 perfustug a lisslie ill which disl rih l1tio n is perfusion rate-lhmn-d amino elnninanon Ol'ClI l'5 . 1111' rate of prt'S('lllal ion 10 til(" tissue is t ill' product of hloud 11m\', Q, ami art erial blood concentrutton, Gk i.e.. Role of pre$entolio n - Q , C A
111l' Ill'! ra te o f ex travasation is l ilt"
-
C~
2
The maximum initial r ate of upt ake is tilt" rate of pn-sen tancn. Q ' C A ' Further, with no d ft-"(1 i\'(' im pedance to 1II000'(' II1("nl into thetissue, hl l)(1(1 and tissue (,",10 IK' "'; ('\1,'("<1 killt"lk ally ;L'IDill' l"Ol1lp;l rt llll'llt , ";tll the ccncentrunou i n l'IlIt"~t'nl n-II011S blood (C",) ill l"
3
when- \'r is Illl' tiSSlIl' volume ;IIJ(I K,. is Ill(' (-"(llIilih riu lIl d ist rilm lioll ratlo (C,IC\,). Furtherruore , Ill(-" fm l1ioll a l rate- of exit, k r , is ¢\1' 1I h)'
It _ r
Role of e xil Amoun t in Iiuue
Q , Cy
V, · Kp ' Cv
whe n' QI\'r is lilt' perfuslou rate of th e tissue. TIll" pa J'itllll"tt'tkr- a distributio ll rat e n nls l;lul with unit s of n-ciprocal tim e, may he ft-ganll'1! us a measure of how rapidly d nl~ would leave the tissut' if till' arterial concentration wen- sud den l), to drop 10 7.NO , It is analogous 10 the I'liminalio ll m tl' constant for loss uf dmv; [n un the who lt, body and. ltkc ehminanou, Iht, kinetics (If tisSllt, rhst n button can 1)(' characte-rize-d hv a tissue d istribution half- lire for which • H IfH o
.. 0 .693 _ 0,693 Kp
le
"
5
IQ/VrJ
Thus, drug leaves slov. ly From tisSllt's Ihal han ' a Il i ~h affini ty (KI') fo , it an d that an.' puu rly pc'rfUst'1l. Suppose no w, tha t tilt" urte rial conceut ra tkm is mainla ilic,,
Iissue ccncenncncn
w
Kp ' CAl l - e - h
. ,)
6
Thus. th e approach 10 plat eau is ddt'rlllilll'(l sul,'I)' hy lIlt" liss\lt' distributkm ha lf-lift" In
.40
DlSTiIBUTlON
CHAPTf l11Q
01)(' half-hf.." ti lt' tiSSllt' conrent rution is 50% of ils plateau va hn-; in two half-hvcs. it is 75%;
and
!i()
0 11.
To app reciate tilt· f()rt~oi n~, conslder ,11(' events dep uted in Fi~. 10- 2. Slltl\\1I art' plots of coneentrution in various ttssues \\1111 time d llrill~ tilt' maiun-nauee of it constant art erial concentration of I mWL. First l'tJllsid N plIl\t'l:\ in whit-I. tilt, K r vahu -s of a d m~ in kiilsi<-· principles . ~m llt' ly. hot ll ihe approach towan] equillbruun and tin- loss of dm~ frorn a tiSSUl' take lon gl' r tilt' IXlo n ' r lilt' 1N.,rtusioll and Ilw grt'atN lilt' p
Permeability Umitation A pl:nJleahility-rdtl' limitation arise s particularly for polar dru gs diffll si n~ am ISs li~lltly knit lilXli{llJ memhram-s. as demonstrated in Fi~. 10-3 for 111(' p;.lssa~l· u f compounds into till" ce re brosp inal fluid . In th is study, till>couceutration of (';u:1J d m ~ was un-asun-d in ce reh mspinal iluid . n-latl vr - to that in plasma wate-r (unbound], wuh tillll' roll(J\\i ll~ attaiurucut and maintenance o f a constau t p lasma conccutrarion. Diffl'n.'l1l'(·S in (',lS(' of ('niT)' an' a
A
aN, (mUminlmlj 4
Kidneys
~
S
05
c 0
~
S
K,
5
5
4
c
~
0
E
~ 3
Brain
g 0,5
'"
2
~
u
0
c 0 <.>
<.> Q ~
~
0.03
Fat
0 ~
Q ~
~
~
0 0
2
3
4
Minutes
2
0
~ ~
~
B
5
6
0 0
1
2
3
4
5
Hours
t'l lt , 10....2. I r .li,tnl.Illio" i. l"'n',-,it.u nl h·-limil... 1. tilt.' lin... til lI,at,l, . 'C! "i lih riu ,n ill Ih t1'·n lr.llW"" wuh hil l(' ill r..l o( ti m ... JrnJ:' "~Ih ,lilT"n'1I1 ii., ,-;oh M" "f I . Z 1 5, n .. p' 'C1i.... ~·. S oh' II..• ,lilT.-n -IKl" in li"M' x .,.]... IIf A (min ) ;I.IKI 8 1llr l,
<'OIM't..
1.,...·
6
CHAPTE ~
,.,
10
fund ioll of holh lipid-to- water p artition t'()(,[fjcit' nt and deg rt'(· of kmlzatkm (Tah l(' 10-2). tln- un-ionized dm~ penetrates brain. For example, till' pa rtit ion In('ffidl'nts of salicylie add allli pt'nt uha rhital arc similar, )1." the time rt"flu irt't! to n-ach d istri lmliou ('qu ilih ritlnl is far shorter for pentoharbital thau fnr ~tlkyd k uctd bcc ause. Ill.'in,gllll' w('aker ad d , a ~rt'il t l'r frotl1juu of pentobarbital is un-ionized in plasma, pi I i A . \\"ith ]arj!t' di!Tt'rt'nl1.·s ill pe -rtusion and permeability of va rious ttssues . it wo uld apl)('a r III ht.' impossihlt' to pn-dlct t i s.~IIl· distnbunon of Oltioll , tllt'n·hy si lll pli ~\i n~ the situa tion and allov,in!!: souu- (:Olld llSion to 1)(' drawn. Conskk-r. for examp le. the follo\\ill Jt question : -\ \ 1IY, Oil IIIt'a.~lIrillg tolal ttssru- ronce-ut ratiun. dOI'Sthe gl'llt'ml anl'stllt"tic thiope-ntal enter the brain much mort ' m pid ly than it d()('s IllIlst,lt' lissut' ; ~1.·I, for Ill.·nk illill tlll' op posilt' is rrue?" 111l' explanation lit's in th e propertk-s u f tll('S{' dmgs and of tissue membranes. Thiopental is nonpolur, lipop hilit, and , hd nJt a \~1.·ak add (p Ka 7,6), only part ially lontzed at ph\llIa p l l . A\ sudl . its t'lltr)"inlo both brain ami muscle UtX.... I TS l1.·;uli!y and is perfusion r ate-limited. 5 ill('(' pt'rfusiu ll n f Iht' brain , particularly ~rdY matter, is om- or t,~u orders n f s ll~est i llg; that only
.111:' 10-3. F..tuilih....lio" of .Iml:: in II..· {'('n,I,,.... . pinal Auid "ill, II.... in pt..
Thiopental
1.0 Pentobarbital
0.8
k'1>ln-LoIi".ry, m ...l""llh" ..'I::I.... '1 tI..· .hK~" (R.~
,lr;r\OoTl fmln tho- ,Lota of H,.. " li.., R-'L 10:" "1, 11., ..,.. I s<'-n:lllk.. r. L S.' n ... i"'p'>rt..,,,.....f .b.. .. " i;tli<'" ..... ,-
Barbital
0.6
.I ;""t """I hpMl .. ~ or hihty in inf!''''lK'inl::tI... pa.. >;l. E.p. n...r., 1':»'20-2.'S , 19fil1. C.
0.4
SalicyliC Acid
02 Sulfaguanidine
0.0
j<2==--_
o
_
20
-_~
60
40
80
Minutes
T.It •• 10-2. Physlc_ ....lc.1.....perti_.1MI TI•• fe, Cere..... I. .....I.. c._.IttnrtI... to a_ch so,," ef 1".lIllN1u. V.I_ ' - hlectotll Atltlle c..IN>. ....... of FI,. • 0 .3·
'
"
""-G
Thiope<1):J1 PenlOborbi):J1 BarbilCl Solqic acid
:
. ..
' 1; "
,~
~
06 08
r5 30 .>
Of" "1' ." )I ,',ICU;!~
' .. ,,;W
~.
70 8 I
SuIIogvanidine
PH1TO'j
06
0004 10
10
'0," .,,!p'''-~
,"'.0'1'
33 005 0002 0 12 0001
~ II!'" ".
'
p~r ~
cosuc ,N'
'" ''''''
,\
"" 10 "'CH
"'" ........ """"'"
C<
20
1.4 d
0 042
4
00012
00005 <000 1
27 115 23 1
-S-'" c....-,._loo..,..,~ 'Ooo;,,,,,,,, . . .
,,,,,,,.,,,F'9
'*"9' J ~
I ..,
I()'-JG"d~.C "' M
n...
11j21~ -2U
"I_.....,..l'<'d
"P-., ~ .-........,
1<xe<>,OJ . !l
IQ~ Q
~"""'""_,J,*,""""....,jb1o
"2
CHAPTER 10
lIIa~J1itU(lt · ~n' liuut atiou. A pe -ruu-ability-rute limitation simp ly t1t'('f(':l-Sl'S till' rate of t' 1l11) am i ht'III'i' tucn-ascs tilt' ttnu - 10 f('adl di stribution t't lllilih rim ll over tluu of Ill.,rfusioll, W!L.. -ri- tilt' t'lJuilihrium lit'S is ludependent. howr-ver, of whi ch P",(:('5S is rak·lilllil i n~. If the - urterial t'tllln'utraliol\ is mainl aillt"tl lnl\~ t '1l0l1 ~h. lilt' uubound eoucentruri.. J1l iu tisSllt' IM'('tllllt'S till' sauu- as tluu in plasma. Scnn-tum-s. however, Ihis t't lmllily is uol 01.. ....."nl. HI'.I-SOIlS for lack of t'q ua lity indudt, lIlaill!t'mll\('t'of sink (,mtlilio ns hy IIwlalMllislIl, atii\'(, tran sport , hulk How o f Interstttial Hutds tlmlll~h both I~lnphalk dllullwls am i ducts. ant i pi 1 ~ratl i t 'llts acros s e-ll nu-mbmm-s. I nt"' lll al i t~· munbound eonce-nt rutjon is frt't !llt'ntly nhst'rvt 'tl in till' t" f1'h rnsp inal fluid ft' lati\'{' 10 plasma for laTKt'llt,lar molecules. (" ~" lllallY an libin lil'S. TIlt' most likely explanation here is th at thr- mit' or fluid forma liun is sllffid t'lIll)' f,!-si am i lilt, mit- uf di ffusioll slllli<.'i('ni ly slow so that tilt' n -sultiug eouce-n tra tion. t'\ '1 '1\ 011 slt'ady stan-. remains hell J\\' that of lilt' di rrusihle unbound d m g in plasma. Another example is Ihal uf till' d istribu tion nf alhumin ill Ihl:' IltM.ly (Tabh- Hh 1 ), Albumin sllJ\\'ly diffu ses a('mss ti lt' t'ntlulllt'lial linillh'S !If lilt' ca pillaries . 11\(' hulk IIm\' n f \\~lkf in the inlef!ililiill II llitl.s alltl lym phati(' \'{'sst,ls pn)\idt,s a IIlt'a ns n f rl'lI11 J\ill~ alb um in frnlll Ihe tiSS\lt's. 11l1' rt 'slllti n ~ tisSIlt' ('tlnt 't'lIlmtiun is m u<.·h IM·ltM' Ihal of p l.l-~Illa. Alhu min also d ilTusc s inlo I!le {'t'n' hrn spi nai llu itl , hul tht, r.lft' is so sltM' ('(Impan'tl to Iht' mit· o f prntlll<.iiun of tilt' fluid tha t thl' t'tlll('('nt ralin ll is \i rt uallv illllllt';l-,>u rahlt" \\111:'11 thNt' is a hn 'akdm\'tl in llit' blulM.l('i' ft'hrns pillal llllid barriN, as t~'('Ilr.i for t' xamplt' in nlt' nillglt is, alhumin is fo und in tilt' lIuitl a..s a n 'sllit n f an ill('f('aSl't1 ra lt' of t·nt"!)·.
'.ltl. 10-3. DI.trlltwtI_ ef AII__I. I..... ~
InllOVOXuio, F',, ~
E.1Iovox u!a,
"'~'" Skin
'MO Go'
Ot+>e< ,,,,,,I
I, MUe ~
lOlaI body ~~""""~
' 40
43
50
23
40 2
7.7
8 110 210 350 s....... ~ " Iho ~ "'-
'4
5 3
2"ClEd Vei l f'"'-:ji:'l'I W ........... Noo,o, v(ri ~
,.3
CHAPTEI! 10
EXTENT OF OISTRIBUTION M ulnph- I'lluilibria rxvu r within plasma when' t1n l~ (, III hind 10 carious proteins. I'Xiullp lt,S uf which an ' Ih h-t1 ill Table- ll ~ . Add k dmgs (,(lllIllllJllly hind 10 alhulllin, till' most ahundant pl,l'1I1a protein, B;lSi(' d m j.,"> oftt'n hind to a i-add gl~'l'op mlt'i n and to lipop ml t'ins. I'mll'illS, '1I('1i ;l" y-glolmlill, transcortin, fibrillogt'n , and Ihyrnid-hillliing glohulin. bintl ~ p. 'd rit· tn nllllllllllk n ; ~Irihllliflu \\ithin ,'a("11 ti S~I W al"':l iU\'llln ... 1I1l1!tip ll' l'(lllilihria Ti ~ slll' tlislrih lltiHll cau ill\'lll\"(' both him!;ng 10 " \\i dt' \"Irit'~' of subs tances and 1~l rt i l io ll ; lIg into fal .
Apporen. Volume of Distn"bution TIll' t'tJ!lt't'nlrJ.l ion ill plll\llla udl;t,\t"tl after distrtbutfon is complet e is a n -sult of till' dust, "d minisl t-rI"t1 alld IIIl' t', It' l1t of I;SSIl" di stnlnuiou. Hecall [rom Chap. 3 that. al equilibrium , lilt' extent of dislrihulioll is dt'fillt"t! by 1II 1 apl~lrt'llt volume of disirilllliioll (\'):
v _ A mount in body at equilibrium '" ~ Pla sma drug conc entration
7
C
111is Ililmmt·It'r is IIs,'flll ; 11 rt'!aling amount in hod y 10 plasma conce-ntration, and tltt' ( ,(lIIn'I"\I ' . Hccull, also. that volumes of dislribulion varv wtdclv, \\i lh iII11slra lin .' \ 11I u " s mn¢ng From :) I J':11 kg hody wt'ighl 10 ~l),OlJ() 1}70 kg 1~)(ly wl:ighl , a \1111lt, far in l'X('('SS of lulal hutl\' si:t.t'. Kllo\\i ug ptl\ l1la \11111111('. \ 'r. and volnuu- u f distribution. \ ', til,' Iraction uf drug in h.)(ly ill am i unlsidt' ph sma ('an 1)(> eslimah't l. The amount in plasma is \'r ' C: tl.t' amount in till' 1)( )(ly Is \ ' . C . Therefore.
V
fraction of drug in body in plasma .. ~
8
It is ,'\idt"lIll hal thl" la~t' f tilt' volume of tlislrihulioll . tilt' smallt.'f is tln- fradiull in pI.L\ma. Fur .',amplt,. fur a IlrtI!-': with It \11111111(' of d istribution of )(X) L.. only 3% n-sldcs in plasma. The n 'm ainin!-,: fmditJII , ~ H'II I~' Froction 01drug in body outside plasma -
IV -V V~
9
lnchnh-s tlnlg ill the- hlut)(! o -Ils. For lilt' ex nmph- considered aho\"(', 9i 'J, is uulsidt' plasma. this fmdillll run 1)(' n 'adily dceenmncd. tln- act ual dislrihution of dmg oUlside p!.L\ lIla cannot . Tle- n ',NIII why tln- \1l111111t'of distribution is an appa rent volume an ti wby its value differs alltlJ1lg d nl ~s lIlay 1)(' appn-ctan-d by (,o l1s i tl ('ri n~ the simple model showu in Fi~. (().... . . :\ltl u lll~h
Al bum,n u , Ao::.d gfycopoo!e,n L ,popoQl(>ln~
CortIsol bond,'"'9 globulm (~on~ortml
67.000 42.000 200,000- 2.400,000
0 4- 1.0
53.000
003-007
500-700 '>-23
35-50 VO'lObie
0 ~1 4
'44
CHAf lH 10
In thi s mo d el, dm~ ill tilt-' hexl)' is enti n'I)-' aC"(11111lIc'(l for in plasma. o f \U]lI I1W \',.. ami Oil(' liSSlI(' com partment, o r volume \ .T' AI distrib ution ('tluilihriulII . th e amount of d rug in e ach
location can ht· expressed in terms of plasma concentration. C. volumes of plasmu aud tissue and distribution rat io, as folluws :
A.
Vp ' C
+ Vr ' Kp' C
Amount in pla sma
Amount
10
in tiuue
And sinn' A = \' . G ( Ell. 7). it follows, Oil d i\i tli ll,l!; the equation abow Ii)-' C, that
v-
V, + Vr · Kp
11
l11t" pr oduct \ 'T ' Kp is the appa rent vulunn- of a tisslle ,;ew('(1 fmm measun-ment of <1m,!!; in plasma. 11111s, h)' ('lpandin ~ , ht, Illodt'l ln ('mbmn' all tissues of th e hod)'. it is M"('l1 th'll th(· volume of distri hution of a drug is till' \'U I U lIll' of plasma plus the Slim of tlu- apl);lfCnl \ l , I IIIII('S of distribulion of ('IK, 1i tissue. For SOIll(" lisSIl(>s til(' vahn- of 1\,. is laf'KI'. which explains why tilt' volume of d istribution of some- dnl/-.'S ca n hI' much ~rt'at N than total hody slzc . Fat, for ('xampl(" occupies appmximall'l)' 20% o £lM Mly \11111 111(". If tln- K,. \"i.IIIt, ill fal is .'), t11(' 11 this tiSSIW alnll/;" has lin app
. ·IJlt.
Plasma
Tissue
Amount
Vp'C
Vr' Kp'C
Volume
V,
V,
10-1, n ... ..If...i " f !i"".. h; ", I;"" " " "m" .L\l rih"hnll
i\ , lIu'lr.tl.~I I~·
.. ,In'l: Iha' .Ii'l ri lo",.~ 1..1Vo'~'"
rl....m;o ;o,,,I;/' ti,,,,,,,n,,· r'l~..i" lt l(i<' ..J1" ",,~ ;on' \',. ;tI1t1l·r- rMl.odi"'~'. At "'I" ihhri" m !I... oIl1 ltltltli " f .In,,, in ....1-11 Inulh' Kl liryM·,,,I. 011 II", '~I"; lil ,ri,,,n .lislnl" 'I;"" (p;o.rtitinn) rolli<•• " ,.. II,,· pia,,,,....,ItI tI", Ii ..",· ,"l" ",,~,
. n" Ii", pla. m.. ('>IIl""Ir.di,," ,
CI-W'TE Il
14'
to
an.,mK.) ' and precision. uud an- l"oslly. ~U11l't1lt'less . it is helprul to dc·fine an unbound \l llu II W ur d i~ lrihll l i(Jn . ,",fl.
Vo -
Amount in body 01 equilibrium • A Unbound p1osmo concentrolion Co
12
whk" permits 11ll' amount or d m ~ in lilt' hod y 10 he n-latcd to 111l' unbound dnl~ roucentr arion. S ometimes whole hloocl l'lJlIl"t'lItralio ll is nn-as un-d, ()m1 ' again au appmpriall' \Ullllllt' u-nu. \'" . run 1)(' dd im"tl. :\alllt'I~·. Amount in body 01 equilibrium A Concentrotion in whole blood - C b A~
till' amount o r drug ill hody is i1ltIl'IIC'mlt'nt or till'
Ect~ .
~ i lt ,
13
or uu-asun-nn-nt . it rollows from
7, 12, anti 13 thai
lA
111t' values or tIW!it· volunn- n-nn v l'1" 1 d ilTt'r markc"tlly ror a ~\·t 'li drug. 111(' u-nu must Ortt" 11 q uotl'tl in the lite-...a ture is ba.\l,,1O il 1II1'1l.'lm 'lIlc·nl or dOl~ in p la..mm [i.e .• V). Examples or t1 0l gs with di lTc'ring value-s or \' an' ~'1.'n in Fi ~. 3-2 (p. 22 ), P fas ma Protein BindinJ;l:_11l(' prtucipal eont-eru \\il h plasma protein hincling is n -latt1.1 to its ' -dria hility \\i lhin and alllllll ~ plllic'lllS ill vario us Ill('m pc'lIlk ~ 'ttillg'i . 11](' d('~rt't, n r hi ll di ll ~ is rn'tIIlt'lIl ly t'xp n'sSl't 1 as the Iimil ill ~ ,miles o r 0 and 1.0 . Dmgs with
bound-to-total coru-entrution ....lIio . 111is mlio h;Ls m llll's l-,1Jl.'alt'r than 0.9 an' sa id 10 ht' hi ~h l~· IIC IUIIt!. As stated previou ~ ly. unbound, rather tha n bound. l'(lIll'C'nlration is rn" IIIt'ntly IIInn' important in Ilw mpeulit·s .11w n· rnn ·, Ihe [ruct ion o r dm~ ill plasma u nho u nd . j u , 15
is or gn'alt-r utili ly tha n rrat1iUll hnlind . Oh\i ou "ly. onl)" ir j ll is l'tlll.stani Is total plll-~llI;1 conceutrunon a ~nod mensun- or e ha" ~t·s ill unbound dm~ cnucentration. Appn»unate values o r [u usually lLS~K'iah'tl with Iht'mpy rur repre-se-ntative dmgs un- show u in Fig. ro.s. 8 i nd i ll ~ is a run l1inll of tln- affinil), or tln- p rotein Ior tht' d m~. The affinit)· is c:ha rat·· h·ri7J.,,1 bv un ussociut iou constant , K.". nt '<."ltll ~· tilt' 1lI1ll,!)('r or hindin~ silt'S on a protein is lim ite'll. hindi uJ!; al....) depends on tht' molar t'()llt'{'utmlio ns or bot h dru g and prou-tu. Fo r a single bi lltli n~ silt· O il the pron-tu. the a.ssoc;jatiull i ~ s i lll pl~' suuuuurized by Iht· foll......iu!-t n -act ion: Drug + Prote in
~
Drug-prolei n complex
16
Equilibrium lila)" lie e ithl' r 10 tjn- ri ~h t o r 10 Iht·lert. lI i ~h a lfinity, or course, im plk-s thut {"Illilihrilllll lh-s fur In Ihc' ri~ht . This is a n-latiw statemvut. however. as tlil' ~fl'al l'r tilt' p rotein concentration for a ~v('n dm~ couceru ranon. lIlt' ~n'ltl l' r the bound dnl~ t,(IIIl'C'n· tration am i lilt' l'tmn'r.'\(·. From 1II1L~ S law conshlc rations, tht' equilibrium is ('xp n'sSt"t1 in terms o r ti lt· coucent rattons or 1I1lIICIlIIltl-tlm~. Cu . llIlo{'{:up it't! pmlt'i n, P. aud hUlltltl d m~, CINI , th us
..
,
OlSTlI1BUTION
CHAPTH 10
Percent Unbound (100 fu)
100
Drug Ateoolol.lIltlium Protamamide. gentamiCin Digoxin
50
PeniC~ttn
G
TheoPhyiltne Phenobarbllal Carbamazepine QUinidine
20
Verap.am,1
10
t "l l!:. re-s. t..
TI N' {r;M1i1I1',,{ . lnll( i ll
I'rutd" . "n. ~ ..;...·l~
pia,,,,,,
r><~
5
IU ll.. 1
""''''''1': t1 n,1t'
A1tenlanit PhenytOin Tolbutamide. Dwo.1de PfoprallOlol Nrttd eplIle Armodarone
I
OlOlloxm
2
Chlorpromazine
Owepam FUlOsemlde Keloprolen
o..m"m 0.5
Tolmelm Wanann, lbcproten
Ptlenylbuta:zooe
0.2
Naproxen
0.1
Flurbtprolen
17
'nil" ull( l(-'(.·upit'1 ! prote-in conce nr rut tou depends ClII the tot al protein conceut n mon. 1',_ TIIt·S(· h\1I l'UIlI't' n lm liur ls an' n-lated h'j"fil , = PIP,. when- jup is ti lt' Irac tton of lilt' lol al 1II111l1)(' r o f bindi ng sill 's lI1lc)(.·(: Upil'( l. FurtlwrllloH' , l ilt' unbound roncentratfon is I II . C am i l ilt' hOllnd conce-ntration is (I - fill ' C . Appmpriatt'ly su hstit uting mto E ll_ Ii. it tln-n-fen- folhlw" 111)lm rt'arnUl!{{'m{'llt thitt 18 From thi.. n -lations hip rlu- value of f ll is ~'l' 1I to depe-nd Oil lilt' tot al protein concent r atiOll, it.. illllsi rall'l i ill Fi~. 10....6 fur lilt" hi lldill~ o f pr opranolol to u l, add ~1>l.1 Jpmft>i n . \\ 11t'1i frl is ..mall « U. O. Ell- IS is a ppm' illla td y Il l1\" ·fil,,· P,), Bv laki ll ~ tilt' ra tio o f th is {"( Illatioll for lI on ll al allli ulten-dt."IJ11 t1ilio ll". tilt" vahn- (If f ll ifr/ l wln-n tln- concent ra tkm IJf bi ll( li ll~ p m lt>in is aln- n -d (P,') is, L ' ,.
~
P,
,
? .
L
,.
19
CHAPTER10
'"
Conskk-r, for exa rnple the change illIII expec ted fur ilmpmf('11 ifll ::: O.()().') , it dmg IMJllnd primarily to albu min, wlwll llll' albunuu ceuce-nt runou is t1t'(·rt'l.LSt"l1 fmm 43 W I. to 2S w L nit" [ruc tion IInlMlIIlIl1 is expecn-d to ill(:n 'a\t' to n .l)l);"; , Usually, o nl,. a small Iractron (If the llvailah lt, s ilt'!' 011 h inding pron-ius is occuptod (f " I' "" I ) at tjn- t1lt'rllp('ulic t'Ont'C'nt ra tiullS o f most d nJ ~s; the Frac t ion unbound Is tln-n rd ativd ,. consta nt at a ¢ \'(.'n prot vin concoutr atton ami imlt' I:M'm!t'lll of
C . Cv/ Iv
20
\\11('11 c(lIlt"t'ph lill i7j ll~ d t.· pt'udt·IIt'), and flllll'tin nalily. th ili equation should no t hI' n-a rr.Ul~I ,(1.
Tbeue Rindin~. The fract ion o f t1 m~ ill botly IUt.·al t'l1 ill pla.\ ma depe-nds 0 11 its hi ll( lill ~ 10 both plusma a nd ti.'iSIl I' t'lllllpOIlt'llts . us !'IUI\\11 St.·ht·mltlk l.llly in Fi ~. 10..7. A t1 rt1 ~ lIlay hlt\'l' a ~n'al affiuily for plastnn p rote-in s, bUI lIIay ... tillll(· lut'
.-'It. 10-6.
•
Control Renal .. Arthritis 6 Crohn's • Cirrhosis
0.20
,-a lii."
0
0.15
('('1",.h'; n ill 7loi p.d io-llll III;lh ,-.uir.. ,~ ,li"'·..."'''' ;oJ .. 1in I..·..hhy' ,, >l uuto...·n . n ... Ii, d r- , thru,,):J, II..· "1 '..... ·nh tI..· n·I"lio ,,,,hip 1'"-1 1f" ,", 1-:'1 III. 11' _ i"~ .. \llI, ,,· or l l I JIit ( " .~ X HJ"! / ",,,J,·) f,,r ".. ,11n, " ·I;I" I I, I. ·..... lII.ot uI' l,l 1· ..,1 e:~ t.. '1"'''dll
,1..,..
~
c
~
B c
::> c
0
•
~
•
.... s 0
0.10
•
mw'J , - 22.7 ",\I ). m"'1 lnr.oll f"'tll To...-r. T.S .: Implk-..tio:II,. III" "",..Il'd pI.o..tllll p rol..i" 'li,...li" :;: ill
(I
o.
~
~
0.05
o
06
.\--~
o
__
•...... ~I .. I.. ~. I n : 1' I"o.rm ,"'Olthll' ti o: Il.a ~ i . fur D n ' lt
0
Plasma
Tissue
Bound
Bound
Unbound ~ l-
T n ·all,..·" I. E.lth..1 loy 1. :1_ Bt·, S , \1 ..".II.t.1. ;oJ .. 1 1(:, C;" ml"·I1' 'lI:[itl. R~ , P",". S · \·"rL. 1 ~1. Pr' 173- 1\1.1. Ot1¢n.J tLt .. f ", l r.lty. ,",,\I .. Bt>flo:4. ( I . ( ), Lar·( :t'<,,·.... J"h.m Il. C 1Sjo"I" ,t . F.: I " . ,·n·.....1 pLo." 'liI p IMn I>lt.. p"'l' r..t .. .lo ~ ;oJ .. 1
or.i..
~_~
1.0 2.0 u 1·Acid Glycoprotein (gil)
j r _~
11..· frd<1'"'' u" I. .. "K! " f pn 'lmu...lo>l
"itl, ,I.., pi..., ,,,,, t . ..... ... I"" ji' ''1 "f ,, 1.......,1 ~Iy .
1l Unbound
3.0
t."" .or
.·hl.. rl,",u...nt... n li..'. '11 ",. •li.. -a ;,..I0..... 1..10.... · Ii",,, " r pl..,t".. a r lldd Iit])·."t''' f.·in , S . En I:I, J \ 1...1.• 29!J:I 4.n- I ~. IWo!!. Ro1'""Io K... I .....ill. I..·•· mi" ;.-,,, ..f tu<'..l 1,,"-•.)
"·IM;. 10-1. .>.I " \"ihl,num_ II... ,Ii" rih" ,io:,,, "r .. d nll: IIIit hill tI..· , I)' ,J,,,...-ML, "n hi",lh'l: In I" ot l, pt..., ,,,,, I'"" ,.;tt lliu '... ('(>lnl""" ·III\. In ,I... "" . ~ -I. ""Iy unl""" ..1" n'le i, .·nl,·riltlt ..n.l l.·.." "..: , I,,· I't..'tllil ..t,,1 1i"" M' cnmI"'I1"..-nl' .
."""",.c.·o.or
D1STPI!llITlON
'"
CHAPTER 10
tiss\lt"has an affinit)"{...vn ~n·ah- r than thut of plasma. Unlike ptl~lll a h i lld i ll ~. tisSIlt' hilltli ll~ o f a d m~ cann ot 1)(' II lt'a~Il H'( 1 dj rt'(11~" Tlu- tiSSllt· must II(' disrupted. rt's ll lt in~ in Ill(' loss hi lld ill ~ is impm t an t ill dm~ di si rih uliu ll. T tssue hilltlill~ ma)' II(' inft'm'(! (n JlIl uwasun-nn-ut of d n l~ hi ndill~ in plas ma. {;o llsidN.
(If its inh'Krily. EW II !MI, tissue t·.~. ,
tilt' fnllo\\ing mass-balance- n-lutinuship.
A mount
Vp ' C Amount
in body
in plo sma
V· c -
+
Vrw ' CT\IV 21
Amou nt
oo tside plasma
ill whi<:h \ '1W is til(' aClllt'()I!S \1)111111(" o ulside (If p loLslIla into which l ilt' d m ~ drstn bun-s alltl C rw is tln- t:om 'spo nd illg IO!;11 d m g concent rat ion. Di \'idiTl ~
hy C.
v
Vp
+
Vrw ·
fI»: c
22
Appa rent
Volume
Appar ent
volume of
01
volume of
d islTibu tio n
plasma
tiu ue
Ih'(~.Jllhat ffl
= Cu/C. Snuilarly. fo r Ibe li ~~\ll', fiI T "" C"J /C nl"" Gi\'l' u lha l di ~ lri"llt i on tlu- un bo und couceutra tions in ph~Ill;l . e", und in 1 i.~MI{·S . Gil.,. are equal. dll..' 11 {~ llIi l i b ri m n is adlit"\"{'(1 whr-n
23 whid l Oil
~ ll h~ ti l ll t i n~ int o
Eq. 22 yields
v_
V
p
I-"Ilt. 10-li. n ..· ,..Il" ...· " f di"rih"h , "f ( of- )'1'" " I'ra,..01011 , jo'(10 Ie, .....1 in 15 pal;"'nh (01 "'~l " clln ln it' hq-.alit' ,Ii..·......· af" 'f"" Lv. 1.. >1". (40 "'R) .1 ( of- ).p"''I'r..'......1. (I>ala fn " " Br.u.. ~' . B.A.. J......... J.. and Brill!. ,' E.: A 'h " ~' ,I fad..", '"H,,,·,rinR .1011: ,1i,!",..iI;",n itt . ....n .. 'it· Ii...., di.. ·....•• ,, \ittl: II..• " ...It·l dnll: ( of- ).1'" '1 ,1'1.. .....". 1'Ir. J. Clin. 11"'n n..... .I.. 3 :U1-249, 11176.)
+ V ' -Iv rw lv,
24
800
0
600
0 0
400
0
0
0
0
. 00 .0
200
•
\
0
0 0
0.1 0.2 Fraction Unbound
0.3
CH.APTf ~
..
,
10
From this relat ionship it is wen that tilt" uppan-nt volume (If distri but ion Increases when
l u is in('n'aM't1 am i t1 t'(·n·;L....'s \\1Ienjilr is lncn-ased. To appr('dall' tilt' n·lat iollsh ip in EII_ 22-24, cous hh-r the data for p ropranolol show n in TIlt' linear n-lat kmship be-tween \' and jil 1I0t only Indicates thai "nt/jilT is ('flllsiant, hilt also that d ilTert'n('('s in hin d ing o f pr opranolol in plasma acco un t for most of ti lt' variation oh""'I"\'('t1 in us volunu- of dlst rlbut rou. Tlu- relationship t'xpn 'sS{'t1iu Ell. 2.1 exp lains why, h{'<.~IlN' o f p];l-sm
such t1 m~s . Fur d m~s I)f h i~' l molecnlur wl'i~h t (g:n ',d er th an ap p rtl'illlatt'ly 70 .000 WllIoll' ). extra\w.t.'ular distribution is wry slnw tn nonexistent . For sUl'h dm~, III(" volume o f diatrihunon t1W Il It'nd s to apprtlxilllalt· that of plasma . 3 L, A ll excepnou ca n occ... 1T if tilt' mac romoh-c ular drug hin ds to l·m lllt ht· l i al linin ~s wit hin tilt' vascular syste lll. Fur d m j.(s rhat an-b ound in m-ither tlssiu- uor plasma. till' volunu- of d ist rihuti on varies IM'tW('t'll tilt" t·,l ran ·lllilur fluid vnlunu - ( 16 I.) :lllt l tilt' lotill l)fltl)' water (42 1.). d{'IM'fl( li ll ~ on lilt' d{1-:n't· In which the d m~ g:ains acces s to 11ll' iut r.l('t·!Iular 1I11itk Exampl{'s of dm h'S that t1i strihlllt· in total lMMly wah-r are caffctm- and alcohol . IMJth sma ll molec... rh-s that p< l-SS frt't·ly t hml l~h nn-mbnuu-s.
SMALL VOLUME OF DISTRIBUTION Mod.1 T Ilt' m(MI!'! exprt'sst'tl hy Eel. 2.1 is con ceptually useful. hilt it does not take in to al'('1Jtlnt that pl,l-slIla p n m-ins distnbun- th rtlllg:holli extracellular fluids, ,LS slltl\\1I for alhumin in Tah lt· 10-.1. A IlI(Mll'I is th erefore Il{'('tlt'tl 10 d istin g:u idl, ill tissues , 1){'t'.\l"{·11 billl lill ~ to p l'l-sllla protein ami billdin~ to otln-r constituents. 11lis nr-ed is pa r1it'II"r1y Wt'at for dm~ that hind to a ph sma p rtl!t'in and that have smal l (less than 0.2 [ Jk~: 14 1/70 k~) volumes of t1islrihlltioll. \ 1uch o f tilt' d m~ in lilt' I)fMly is t11t' 1i IMlIIlld II) tilt" phl-~ll\a pm lt'ill and lilly dlang:t· in biuding: or in the distrihutioll of til(' prolein ("an substa ntially inllm·lIl't.· Iht' dis· trihuliollllf ulllMllIlll1d m g: \\i lhi n illt' IMltl)·.:\. ll1odt'l lo dt'serihe sud l d istri huti nn is dt'rin 'tl in :\ pl'M 'mli>.: I- F. For a d m~ IMuIlld tu alhlllllill, th(' app m'l:imat{· rt'latiousllip !wt'.\l,"{·n \ ' and hi Tl(l i n ~ to alhurn in ,lilt! utI1t'r silt's is V :o
7.5 + (7.5 +
~) Iv
25
wllt'rt'/lI is till' fmd ion llnlMlIllld. \ '11 is tilt' illlllt'OUS \Ull1llll' of Ihe illtnK't'lIular fluids into whidl d m~ distrihutes (tolal a\'ailahll' \XJItIIlll" "" 27 L ), alltl jil tl is the apll;ITt'nl fmd ie)ll unl)fllllld in Ill{' intr'K'I·II 11tlr fluids. TIlt' , i rtm' of this lIleMIt>l is that il p ro\; dt's a m(',IIlS of
CHAPTH 10
150
'lIIaly.{j Il~
Ihl" dislrihution of hul l. d m~ and tilt' pl.l~lI1a pr otein 10 wllkh i t hil\(k Bl'p rt·· S('1l1a!iv(' d", ~s \\; 111 volulIles of d i<.l ril m tiuli It·ss th.mll.2 JA:,g und 10 w hid . this mudt'l is Spt·t.i fil-ally applk'ahlt· an.' ~WII ill Tah1(· 10....5. To Illust rate tln- ulilit}"llf tln- pmpo S('t! mudd . ('(l llsillt' f ti ll" tlal" ill Fi,g. 10-9. s ho\\ll is a lillt'ar n -lation ship hdwl't'1\ \ . ami fll for a sem-s of ce-phulo s porius. T his dq )('mlt·lIl't· lI1 i~ht 11ll\"t· IIl-'(·lI l·xplaillt'tl hy tilt' ~(' I J(' ral l11 ()( lt-l, \' ::: \ '" + " n t, -f ulfilr. as sllllli ng filt dill'S lint var), ,1Il1nng tlw (, ·plmlospn rim . A major pmhlt'lII \\1l1l1d haq , lll'('n noticcdln-n-, ho\\'t'\ "l'f. 111( ' o!Jst'T\'('(! H I l lin it' in n-rcept w ht'Il}it appmadll's lJ.·rn is "j 1170 k,g(n. l l IAgl, a \~III1t· 111111"11 larger th an thl" ptl\lIIa volume, \ '". u f:3 I.. T Ilt"u!Jst'fYaliollSart ' much hdtt'l' ('xplail\('(1 b~' tilt' p m poS('(1 1I11111d . T1lt' d ist:rt'P'Ull'y hdwt'('n tln- 1\\11 nllll ld ~ l il'~ in 111l' distnbunon o f tilt" plasm a protein . T ilt" pmpl)S('(I IllIII)I,1MlAAl'sls that ulluuniu is till' major hilldi ll ~ pron-iu for tht,S!;, ant ibiutil'S ill Ihat Ihl)s(' 1"l'ph a.lo~pori llS Illat ure t i ~b l ly IlIlIlllti han ' distnbunon dm ral1l' ristil'S ill 1'\I1II1I10n with alhunun. 111t' volumes of distrih llliOll (If tilt' 1't'p hal(l~ rN l rillS al h i ~I l( ' r fmd icllIs 1I111111ll1ld , h lJ\\ '( '\"!'r, imlnut e that till' t1m j.. 'S mu st parti ally e-nt er 1't' II ~ or III' INJU nd til S!; )lJlI' 1'\ lmv,l' I'ular st n utun-s . Tilt, extent uf Ihis dis trihunon outside tilt' extracellular fluids. rm
,.ltl. 10-'. ....-_........ Drw•• W .... V.I. . . . . . DI.trlltutl.1I
.. O.2L/k._ .....• Calotet:Jn CeIIlio_one
[).clox.oc,U,n o,lIuniloOl
P"o~icem
CelUfOllime
Flu,bprolen
Prccerecd
Chlo
f u,~ide
CMorpn;lf,Xlm' Oe CloM)llc acid
Ibvprolen KelOproien Nopro.<erl OKyphenbutozOlle Pheny!bvto.zone
$cllcyl><; acid SvKiloO_ezole
C1OJ
Didolenoc Dobutom",e
. '11/;. 10-9. n; \1I1" "M""r ,1;.l rthuli" " "r a .. .. rit... "r ' '(1,1..1.'''1'' ''';'' ..ulil ...oI i1.. It ..:,,·..." '· ",i t I. !IN'
0.3
O ",l lIM",·lh.d tI... \ '11 _ Z7 L
(E' I' 2.~ ). 1".1 ,I" IMoI 1>i". II" Ii.",,· "''''1''""..'1. (f"" - I I. n N' " 1'1,"'....I" ,ri,,, .IN...... an ' ; I t,· f.."id. 1. 2 - ,.·r_ ~ i ". :) - "·Ii,r..,,....·. 4 _ u·r..ulOll.. I.>Io.·. oS - ....· r"t:~ll ill. n • " 1",.J.0I1.;" . 7 - I' M.....I..1"'tn." - " ·f'>I",,II1..·. !j - .,·fl.ui · . liuM'. III - " ·pl.",J.·\ ill. "'IMI I I - ..1".,.....I;,N·. (Dr. "'... fn"" .1.1.. .."t1I>iI. 1 I>:> I), NII.-,'. \ 1.:\.•
;(lNl :\ iltlrti"li:aJ.·. C II ,; Err 1. " r 1'' ''1<1''
TolbrtJmide Totmeltn
volproc cod W e,lo" n
-,
,.,•
rr..1i,," " Uh"OIl Nllu 1'1...",.. p" >I.; u•. 11... ' '',,,. ..r II h,,,' " r 1" '\1 fil (••• J Ii<.. INi "'....·" ,I,,· •.•. 1"...1 1 n.Ld.. " " I,i f" r dnll:' 11t.tl .1" IM>I "",,"r
Ii..u. ·,,·ll•. \ '/t -
P'peo'ac,lI,n
,,~
-v
6
• 4 •" '
0.2
",.
B
,.'
•• / . 5
0.1
7 "
.
,,
,
io
• , .,,""' 'I 11
"'~~
9
\j II "" ()
2
"f"'"
.. 1i,il~' "r "-pl,,,I." I,,"';t1" :\ ' h' i il·Lor.1..", ...,,11· hi" b ,,", " ""i,,,,.. r",", d ...tn i'I ~· I" dinil" .",' "r \! ....Ii<.i".,. ( ;.~], ,,, . "r 11,,,it-ia,,. ur 11'il. It·]I". I;l. ree. PI' , 227_2.19,) .
o +--~-~_~_~
o
0.25 0.50 0.75 Fraction Unbound
1.0
CHAPTER 10
lSI
the- e\tr,ll't,1I1 1Iar \-(IIIl IIl(' ( 1.5 1}70
k~ ) .
hilt (:ullsil!('mhly I(·~.. than total htlll~' water (-12 Ij';(J
k~).
T ilt' 11ll1 1l1111ld \UIUlIll'S o f distribution within the series of cephalosporins ri ~. IC}... IO ill conr rust ((I tilt' tot al volunu- u f dtst ributfun. t1 r,u natie..lII\· dcen-....'i.t.' us the (ral ,tim l 1I1111l 1U II(! is illl'n·'l'>('t i. Fo r t1IUS(' ('t'phalosporins thai an- hi~hly l~lIIlld (low jid , tilt' billtli n~ pmh'in t'ITt'l'Ii\('ly tit ,s lip tilt' dnl~. 11 It' (111l'it'tlnelll't· o ( plasma pmlt'in hi lldin~ lu-n- is tilat a 1I11lcil I.uw ·r amount of tim)!: mllsl ht, in lilt' 1Illlly In ¢ \'(' lilt' sanu- aut imicrohial t·fTt'l1 for IIIO'it· dm ~s with tilt' sanlt' minimum inhibitory IInlMJ1l1ld concentration.
location in Body TIlt' fral-lions of dnl~ in the IMllly that an' in plasma (1lllu ml andunbound ), ill or outside t"d ral'd lular lIuitls, am i ho uutl i ll pl,.....I!l
e, 1.5
n~, 10- 10, TIM' ""IMMI1MI ,,,I" " M" of ,Ih tri . IM'lk,,, o( 11 11... n 'f'l..,j,"IM.rill ' .1M"''' in Fij{. In..i j , .. '(Tl' • dram..lintJh· "ith;la' iI KTl·..... • in 11K' fr.-1i<M' '11l1"MIlM!. Fur 11M·....· ('(,"..Jo"I" 'ri '" "il ll lllllMMltKI '~~ ll ll"" nll Kt , II:n·..I" r lha ll 11M' 1.'\1ra(~,lI llL.r 'p.o<~' ( \'f. - o.:!2 IAli:l "I' II..· t"t ..l l ....~ water (ti n I A Ii:I, himhll ( I n r t u ma I, mlt'in _ (.J."... ~. n ..I'M..... II <~ ..M " r..Ii"" ..f ti M' ao:1n.. for'lll fur a (h" 11 ,1. _1St f'1( 10..9 fflr i<1.~ 'h· fi,,;,.Ii<Ml ,,( 11M, n,""'I."I'''"''' "'MI ,1M' " ..,n~· ..I'
1(5.5)
-a
:5
e2
c
.2 ;; 1.0 D
e3
'C
;;; C "0
Ii..· i" f" nrlo4li<M\.)
4 e e6
~
E ~
"0 0.5
_5 _ 7
>
~
c
e8 e9
~
0 D
I\q
C
=>
0 0
0.50 0.75 0.25 Fraction Unbound
1.0
r.lltle 10..6. " •• ple, ef c.IHIltI_,I. 'NIIld.... PI_•• e..cellflwtl_ ef the Twe Meier PI•••• PTe...., .. WIIlell D-.. allMll Are AJt.M411
HepohC
cirrhosis
Burns NephrOlIC syndrome
Erd-sIoge rercl drsecse P'egr'Mlr'lCy Nlyoco,dtOl info,chOn
~~d'soose
Trauma Rf>eumalC:lld o,fh"l.s
Decrease Decrease
Dec-sese Decrease Decrease Increase Increase l-c-ecse Increase Increase
cI-tAJ'1( R IO
OOSTRI8lJTlQN
wh id, rlu-n- an ' d l ,lIl~l'S in tht' di stribution o f p l,L"ma p r oteins. Ht·lat i uJl sh i p~ to t'akulatt' these Iractton s an ' Kin'JI ill T ahlt' 10--; . Tl n-ir dt'rivatiuns an - Kin' n in Appt'lld ix I- F. \ \ 11('11 rlu- app.lrt·nt volume u f dis tributlon of 11 ( I m ~ i... largt· ( ~n'al er than 50 to !lX) L ), Eq . 2.'> appm xilll
26 whkh is \irt ually tilt' ~1I 1\t' a." tlmt p n -dten -d h, · Ell' 2·1. Tlu- major p rat:tk al app lil'iltioll of Etl. 2.'i. h owt·n·r. is for dm~s wi th small \ Ullllllt'S of dis tribution . i.e., \\i th \~a lues «pproachi ll~ 7..'i IJ';"O k~ (tI. I I I Jl~ ) fur a tlm ~ hound to albumin.
AJtered Binding and loading Dose IAllUliJl/ot do....·" an' /oth" 11 10 rapidly uchir-ve ;l the-rapeutic n -sptm...-, p lltatin ·ly hy rapidly
.
V
Amoun t In body - ~ . Cv
27
111is t'tlua titlll indica tes tl litt CII is indt'I)('ntlt' nl of plusma h indinv; and thu s no adj llstuwTlt in Itllid inv; t10 st' is needed. l 11t' tota l plasma t'ollt"t'nlratitlll do es, of course, c.·h.UI!?:t· \\;th uln-n-d p h \ ma hinding, h ut th is is o f no tlu-rapeutn- con...."t lllt'lIl't· with res pect 10 It l;l
Unbound
on body wale,
Unbound .n edrocellukl, In
42 . lu
e~"ocellulo,
V
Auid~
Au,ds
15 . fu V
7S11+fu1 V
V-75t1+1ut V
3/1 - M V
Bound 10 e~"ocellulo, pl'olEtins
75(1 V
lui
V-35·fu-75 V
1S3
CHAPTf R 10
STUD Y PROBLEM S lAnswers 10 Study Problems ore in Appendi;J( 11.1 l. Dt'fi nt' rlu- h'nns a pp an'n l vnlunn- o f distribution . frdl1ion unbound. lissl1{,· tll-h loIKI \'llui libri uJII distribution rutin, and jlt·rtusion -ml t· ami pl'nm'ahili ty-mtt' limltations in dm ~ disrribntion . 2. TIll' volume of dis tribut ion of qutuacrtne. a dnl~ IKllIllI1 to albu m in in plasma, is about -to.OOO 1.. 111l' Iracuon unb ound in plasma LS o.ns . a. TI lt' plasma concen tration when I ~ of d m ~ is in til(" !Kllly would therefore he
=
IIlWL.
h. T ilt, amount of tlnlg in tilt' IKKly when IIII'
=
plasma cone-entratton is 0 .0 15 mgl L is
1Il~ .
c. TI lt' pe n.'('nl agl' of dnl~ ill l ilt" hody that is: I. oulsidl' Ilu- phslll;t
2. in extn«....llular fluids, 3. IKlllm l outside extnll'.:-llub r fluids
3. TIlt' \"UlllllW nf t1ist rilllltioll of a t1 m g {molecular \\'('ig hl = 3S 1 Wmold ill a ';'O-kK suhjt'("\ is " !l,,,·n ·t'll to Ill' s L. Ind ie ,lt e which IlIIt' (or mo re) (If th e follo\\i n ~ stat ements is (an.') l"tllls islt' nt \\i l h thi s ob",'n ·a!ioll. 111t· t1m~ is: a. IIi gh ly hound 10 plasma p r oteins. b. Hound 10 1,()lIlj)(llit'nts outside plasma and is h igh ly ho u nd 10 pron-ius ill plaxma. c. :'\01 bo und I" plasma proteins . -to T Ilt' lo la l (ll'ft ) andunbound (righl) coucenr ruuons of D m g A folllJ\\ing si ll ~l l' is . doses ure SIlIl\\11 in tilt-' Fi ~ . 10-1 1 and 10-1 2. Sketc h on each of tilt" sa me fiW IRT'S th e ,1Iltid palt-'l1ul rn 's l)(lIldillg concent rations of tilt" d m g whe n a dnuuistcrt-d: a. In l ilt' p n '",'m "l' of D n l ~ B. whkh sigll ifil'O m tly (two-fold l'han~t' ) d isplat","" DOlI!: A (.5n O-m g dnse) fmm tiSSllt' hinding sill'S only.
3
6
9
12
Hours
h. AI a SUhSl'"(IIII'llt tiun- ( 1 I M M ). Il1 ~ d ust·) whe n the jl;l!it' III's serum alhumtn, l ilt' pmlt·in 10 whidl the dmJ.: hind s. is reduced [mm ·12 til 2 1 WL ( (, . ~. , wh en the 1l;llit'nl dt... 't,!ops nephrotic- svnd ronu-). ni lldi n ~ In other constituents in th e IxKly is unafIt'l·!t·d ,
.,.
CH .I1'T E ~
o
3
6 Hours
9
o
12
3
6 Hours
9
10
12
nc.. 10- 12:. .'i . Brit·lly l'tJIIlIllt"1I1 011 1I't' \'cl1idit)' of eech (If I".' fnllcMill1l: ..tatenwnts. it. TIle' t"lu ilihrillllJ tli,tri buhnn rdtio for a dru g h,'t\101''''"11 li\l"T "lid pla...ma i... 50; tlwn.... kR. fun.', ih \1I 1U1Ilt, u f tlistrihlltitm IIIl1st be at least 75 1. in it man wt·iw. i n~ h. .\ elm!: t1ul rceches dtstnbunon equthbnum within 30 min. )"(" ,,110M' ,..111111lt" of tlistrih utio ll in it ';"O-k~ 1Il
,0
n~a lls .
6.
U ", i ,,~
tilt' ill(n nlldtion
i n Tahle l()..b. ~e&lcllla lt·
tlK'
tilllt' n '(luin-c1 fur
tilt"
aIlK MUl t.. in
(",K:II o f tilt" tiSMICOS Ih h-t110 n-at:h 5(Yl o f ti ll' equilihruun vahn- fllr a dn,~ \\.;111 p 'rfusin n r.t1 t'·lilllilt..1 di..l ril ml io ll whe'lI l ilt' art e-rial h lood ("o nl"t' lIl r ,tl i u li is kt-pl constant wit h hill!" t l ~' J:i\;,, ~ a !tOIUli and an appropriate infll,inu). Rank til(' t illl'~ and tI... (...rn·· "pollllillj;l; us..IIt-s.
1"'9'
-"
,...
I(tdoey~
5' ,"
I 4
3 15
12
'0
4
0.0 08 0 0 24
, . DiWlndn !I;l' a \'01111111" uf t1istril mlillll of $ "1 I. in ;I 70 -kj;l; man lind i, 97 % huu nd in p l;l\lIla. ( ;i\'l'n tluu tl u- 1I1lhUlllld dnl~ di..tri butes ....'t"n l~' t1m lll~lloul total hnd,.. water. " lliIt fr.u1inn "f dm~ is unbound in Ihl;'" in!t· n.,·llliLir flui d s? .1;. D i ~(l\ i n h'l' a \Ullllllt" (If d i, lrihulin n of ahout 5S0 1. in ;I 7n-k~ slIhj.'t.1
CHAPTH 10
ISS
, ...Itt 10-9. M . . . PIMI c..e _.I. 11 C
A...I.I
kl
I• •,Ief W
tlc Pw,. 11 Neph
rI.·
VILI
Q
4
:!:.
1HI1enJ. . . . . . . 1. After 0-1
2.7
020 :!" 0,07 36 :!: 14
CI!VI-IlI ', / (hI)
43 • 5
se1um elbum,n Igill 'f..,...~, o f ,,,,,",,,, AM e-.j ,P.....,..., N
c
~MO ~,p .""""-,G
'........... """'"""=. "" ...,...., r~ <.,."'9la<"'"' a..
NoPwcl 1$18-80,1080
137 058 18 125 ~~rJ""'""-'
:!: :!: :!: •
66 0 26 11 65
........ ~
a. C iwll a fml1ion unbo und of O.lln3 ill tile control J!;nmp , es ti mate th e n J ul' expec t e-d in l ilt' llt'p h rulil' ~rn J1lp . h. \\';trfa rill h ;l~ a sma ll vnlnnu- o f di st rib ution. Cak'ulatt' l he expected vnluun - of di strilmlioll if fi' is inl·rt'a.~ 'll to tlu- val ue calculated in "a.~ Hin t: den -n utm- till' \111111' of filft ill tilt' contr ol ~n m p, and a.~SIIllW it is tln- same ill tilt' Iwph m tic patient s. c. I t u I tilt" h.llf-lifl' data 1101 Ilt'l'Jl ¢ \"l' U. could )'011 ha\'t· predict ed till' o!)S('I'\ 't'l l sho rtI ' lli ll~ o f till' vulur- ill till' Ilt'pl ln llit- pi lt it'II IS? 111is condmon usually S Il~t'St s induelinn of 1lll'l aho lislIl.
Eli MI NAT IO N
OBJECTIVIS The leader will be able to : I . Define the loIlo-Nil'l9 USii'l9 boIh 'NOfd~ond eqcctcos: clearance, blood clearance. unOOund clearance. hepatic clearance, biliary clec-crce. and renal clearance
2. Colculate the exnocnoe rene ocross on eliminating organ given blood clearance and blood
flow in rholOfgon . Ascerto,n Irom the volve of it$ e:d rocliOfl rene wnerhefme clearance 01 a drug by on agon is perfusion me-lunued Of is dependent on ilS binding to plasma proleins 4 Cakulalethe IT"IO)(imum 04'01 bioavailobili tyof a d,ug given either .15 bepotc eorocrco rene 01 the appropriate infotmolion 10esnece this vclce. S. Dereemre the biliaryclearance 01 c drugfrom il$ b,le-to-piosmo cceceoeonce reno and the bile flow. 6. Descnbe the role thor biliary secrenon con ploy in drug dispc»'hon , 7. Descnbe where 'iltratiOn. secerce. and -ecbsopeco 01 drugs occur w,min the nephron 8 Sene the ovefoge value 01 glomerular filtration rote. Q Given renol clearanceand binding dolo. delefmine if c drug is predom'nonrly recbsorbed from Of secreted into the 'enol tvbJle, 10 . Anliclpale rhose drugs for which a change in e,rhef unne pH Of uline flow may alter The volve cJ the;, renol clearance 1I ~toin the relahve cantribJlian cJ the renal and exeoreocl roces to toIel elimination from !heir -especnve clearance yol~ 12, Explain the ~totemen t , " HoI I~ile ceceods upon clearance and volume of di~'ribulion " 3
Tlli' ('hill'k r i' tUII('t'n ll~1 \\; 11. c,lilllilliltioll pnl('t" 'l " allli p ilr1it'lIbrly wil l. li lt' l't lllt'ppi o f d c·ar,trI{'t· . III ( :l lap. :1. I). allt l -;. I] It · IIll·l lul(l, .,f, I ' Ml l l i l~ 'i l l ~ t "l.·ara lu 't· wr-n- pre-o-uu-c l. Lh-n-
ih p lr~ .... iul()t:k Il W,l1lillt: h t:iwlI.
ELIMINATION Elilllillalioll t l('('lIr, I " r-wn-tion .1IIt! II wl ahul i'''I . SO" ... drllt:' an' "\(Td .~l d
Otlll'N, I l; Ht i ("ll la r l~ m lalil,' \1I",laun·,. an- c·,ndl 'd
ft 'W ,
".
CHAP!H 11
157
TIll' II1mt l1I1lIIllH lI m utt'S o f dnl ~ rm-tabohsm an' oxida tion. reduction, hytlmlysis, ami Frequently. a drug .\ illlultallt'1l11sly undergoes IUt'taholislll 1';0' s('I."l'mll.'UIIII)('ttng l)ll t hwa~ ..., 111t' fmd inll goi ng 10 each IlIl'1aholitl" dept-'mls 011 tlu- rdath"l' r ates of eac h of till' pamllt'! pathways . ~ I d ahol i les lIlay Ilndt'rgo furt lll'r lIwtaholislll. Fo r example, oxidation , n-ductiuu, allli hydml~...is an' ofh-n follo\\"''1I I';o' a co njuRation reaction. 1111:'S(' re-{'()nj ll~illion ,
adiollS IK'l'U f in seri es O f an' s aid to II(' ,n 'q llt"l,tinl. Becausethey ofh-n (K'l1 If first, oxidati nu, n-duction ami hydml~'!ii s are {,()lnmonly referred to a.s Phase I reactions. ami t' lIIjuF;ations
II reactions. the lin 'r is the major and sometimes (lilly, sin- of drug metabolism. Occasiouatly, ho weve-r , 11 d m ~ is l'xtf'lIsiw ly IIlt'laholi7.f"11 ill one Of mo re other ttssucs . such itS tile kithwp , ski n. IUII/-."' , hl(l(l(l. ami F;ilsl mi ntt'slinal wall, ~it~l)'t,t'ri ll is such all example. Tahlt, I I-I Illusrrau-s 1l1llh' m s of hiot mllsfon natioll (nwtabolislll) of representative drugs. Tht' l )llt hwa~ ... of IIwtabulislll an ' d ,t\..s if!t'1II';o· chemical alteration. Several of rlntrunsfo rmatlons oc x-ur ill the endoplasmio re-ticulum of tilt' lin 'r and o f certain other tissues . 011 h CllJl( ~t-ni zi n ~ t1wst' tissue-s. the e-ndoplasmic reticulum is disrupted " ; tI1the fo rmation of small \"(·sid t·s ('allt'1l mic n A'lI JtIU',Y, For th is n-ason. lIletabolizing l'IIZPJ){'S o f til(' r-ndoplasunc n-tn-nlum an' l'llllt'1l mk n A'lI)JJ1f1l l'fI Z!lll U'S. Dr ug metabolism, therefore, may be ,tS
a
I'h ,N '
(~:Il(" rd"y,
d ,tssif!('11
RS
mlcrosomal a nd noumicmsomal.
IHI
ICi 101
10 1
leI .. ~ro.>:yglvlelhimide ~ Hydfo>
G1vlelh,mode
1' 1
P,ed",iSOtle ---------; . ~ P,ed"'i5Olone
IHI Svccirtylcholir'le -----------1.~ Svccir¥monochoI,ne
101
"Clm>..l" tOI. <>o ~ 1~1.~.fHl~.lCl .~ ,,"' ..,.... ohg>",.., _f'IOOOOb:>I,C ~ _ odo:cted ~
'" c""" _. ~ Jok,,.,,rq '" ~ ",*""","",,,,,,d "'1lO'''
CHAPTER II
lSI
111t' majo r (' 111.)11]("5
n-spousibk- fur tilt" o:dtLltiull ami f('(lm1iuli of d nl ~s ht'lon,g 10 tht'
superfamily of cyt ochrome P4.50
l'1I1.)1IU'S . Tilt' tsozymcs of this family displaY;l n·!alin ·ly dt1!:n >t· of structural Spt'<.ifi(:ity; a cl m~ is ofh-n a ~oud suhslmft · for mn- ('ll ZY'Ilt' hili nol a nother (M'l' also Chap. ) .1) . 111t, l1 J!l!i.('l:IIIt'Ilt'l'S or dnJ~ llwtaho lislll an ' man ifold. Billt nUl sf u n u
h i ~h
CONCEPT OF ClEARANCE of till' t'()II("l'P!S in plm nna('(J~illetit"S. cI.'nnlllct' Il ll~ tilt' ~f( 'a tt's l putt 'lltial for d ink-a l al). pbcauons. It is also tln- 1II0!\t IIst'ful pamllll'tt-r for ti lt' evaluation of un t'!imin,ltiull IIIt '(,..II· anism,
10.. Au..... Organ of IIiooIoatIoo Ht"<.'1t11 From C hap, 3 that clearance is dt·filll'll ll~ till' p rupo rtiollality Iactor rl'lat ill ~ ran- of dnlg elinrination to tilt' pl.l~1lJa (d m gl conceutratfonThat is. run- o f t'limination "" C/• . C, Clearance may II{' \iew("t! in another way. namely fmm lilt, loss of t1 m ~ ac r oss an 0'l'all of clumnancu. 111is lat ter physi(Jl~e approa ch has a num ber of atl\'alltll~t'S , partil'llarl~' in prt"(!itiinJt and ill l'\1tluatinJ.( the elTt't.i s o f dlallJtt'S in blood How, plasma p mtt 'ill hi lll l i ll ~. ('f1Z)lllt' ,It:.1h i t)'. or M"<.·f('tUI)· acu vtty 0 11 till' d iminution of a d m Jt. FiJt. 11-1 summarizes tilt' \"ariolls way~ of \it"\\inK IUllSS hal,U1l'C:' across all e1iminatiuJt0'l',m. I II this scheme, d m ~ in the el imill1ltinJtul)!;all is llSSUIllt-'t1to have n'ad lt'll distribution t>(!uilibriulll; thus, tln- so le n-ason for auv tlilTt'n'lIl"l' bt,tw("('u tilt:' artt'rial and ' ·t'lIllIIS l'()lJl'l.'n tmt iu IlS is e1i minat iun. For all but tI~t' earlit'st monu -nts. thi s assumpt ion is n 'a.'iun;lblt, for the kidllt:;."S and tll(, livt-r, which an' a monJt til(' most hi ~ltly perfused and ht,III.'I.· most mpid ly 1.'tluilihratinJt orgam ill tln- body. TIlt' r an- of prescntanen of a drug to an u'l',m (If elmunanou is the product of hlto.! How, Q. and l,(J!lt'('ntrdtiun ill blood t'nte rillJttill' urterial sitlt" C." Ibat is, Q ' C." . SilllilOlfly, tilt.' r ate at whic h d nl ~ lea\"('s Oil tilt' venous side is Q ' C \., whe n ' C \ , is thl' concentranon in tilt' n ·tunl inJt H ' IIHUS hlood. 11l(' d ilTt.'rt'llet' 1)(,twt"('11 tl l('S(' rates is tilt:' r an- of d m~ extract ion (t'liminalion) hy thr- 0l)!;,m, Role of extraction - Q{C.... - C~
If tlu- ran- of tl nl~ extraction is related to tilt' rate at whidl it is p n-seun-d to tilt:' o rga n,
Q ' C A , a IIst'ful P;lf1UIlt'tt'f, til(' l.'XtmrliOl' mt/II, E. is tlt'rin'll: f
Role of extraction - Rate of pre WJntotion -
T he t'\tm l1inll ndio lit's !)(*t\\'t"('n 7..t·m , wtwn' t'st'1IIX'S pOlSt tht, (J~an .
lin
t1mJt is t:'Ii minalt,
2 IU )
dnlK
CHAPIn 11
".
ElVV\NATI()N
If tilt' n Ih ' of dmg t'xtral1iolJ is n-lan-d to tilt' ill(·tllllill ~ concentratiun ill blood. nn e o htain s, h.' lh '/lllitillll . lilt' \ ;a] Ill' IIr dt'a r,lIlu ' (CIl<tp. :31,
3
Clearance ,.
in l hb instance. bloot! d t'a nu Il't', CI'I,. ",illl't, tilt' ('tJ!ll't'lltmtio ll in hlood is llU"il"'Uf('(1. O n slIh",lit tltill!! Ell :2 into E'I :1, dn ' 1'll1o\\in!! impurtaul rt·lalioll,hip is IIhlai lll'(l:
CL b
o
f
Blood
Blood b troctia n
clearance
flow
4
ratio
TI Mt i"" hlolKI d l';lriUI('(' IIHI.'· IH.' rt'~al't lt'(l it-'" till' \'Ulllnl(' of blulKI Froin wIJil'h all tilt' d m~ wOllld a ppt';1f to l K' n-uum-d pt'r unit tune. For t'xa mplt-, if tilt' t'\lmdiun ratio (If a drug ;I('n "", all o f),tall is n.s and of),t;m hl'KKl l1nw is II / min, 111t'1l all d m~ ill 0.5 L nf lh t, ill(.,( )lIIi ll~ blutKI is l' ffl'(,tiw ly f('IIl(J\I'(1t'"d l minute as hIIKH.I p
1 Mass Balance
~
Rate 01Ent ry
•
i
~
Rate of Leaving
o-tc.c)
Rate 01Extraction 2. Mass Balance Normalized to Rate of Entry
•
~
E Extraction Ratio 3. Mass Balance Normalized to Entering Concentration
,
. ·i!l:. I I -I . 11M' ....I r.'di..n ..f" , lnll1 l~' a" .· Iilllinaliul': "'1t"" tlIKlo'r ,It,~· .•t"h' ''OIkl; . I;' " .. u"'y 1M' (~" ,.;'Io·n·d frulll tiM' fu)MLouM....• 1..1UMI('t'p!'''( II I..J",II...., I. ll M· .... lr....1;.MI of ,lnllo: n..... 1M' "' ,,"'11.. 1fill" frum it> r"I,.. in .IlKI ' MIl .. Ih,' ..'1t"'I. 2. ~ ' '"'w1U:inl1l .. 11M'
~
(JoE Clearance
r"h- " f .·nll)' ro " i
11K' (""'1;'.., ....I ""'1 ''t1. II..• ..'lr 1im' r..tio, 3. ~ "n,w1 i7.inll: I.. II .., t"1'I1·"; n~ (
n ll ....I ;.,,' ..J.
10"". ' '' M' 1<1 ....·u ""'1 for 11K' ,Imll:in 1" n,1' of
(·Io'ar"'K't' ..".1loIo ul It<,.... n..· '~lllIM .t. an' ,Io~ litK..1in E'I" I II,o .,, ¢ , -I,
160
CHAPIH 11
kitlllt')"!' ,mil lro -r. tilt" ;1\l· r.I~(· ur~a ll hloud flOWl; an" 1.1 alltl J.~ Il min (Tahll' 10- 0 , rt·Slk"'l.1in-ly. I ~ · flln · ('t)n si{ I( 'ri n~ dt'anUll' -'(If {I n l ~ I,:,' Spl"'l., fil· o~all s . seve-ral l1UIllllt' n b an' ill nnk-r.
Description of Oearonc, by Organ, Process,
Of
Sitt 01 Meosuremel'
( :It'ar.uI<.'t' (~ III hI.' tlt'..cnbed in terms of the d i llli llatill~ o~an , ('.~ .. Il t 'l l; llk clearance. n-nal dt'." , t o.~ •• 11\(1aholic ck~d. ...a IK,:or ('~l'WIOf)o' d t·arllJ)c., ', F l;rthc·nJMln ·. thed t'a r.mn.' "al llt, tlt' pl'nds u n tlK' n ' f" n' II("I:' Buid . 11l1ls. to lit· "pl"l;f}l" lilt" d t·drdIK'l.· o f if. dm ~ t·lilllilla fl..1., .,!t.. I" , lut'I"lw,lism in 1!K·lin ·f, t1S in~ pla...ma concentration nu-ar..u n-na -nts ",u nit! then 1M' Il«'flitliC mt'fahnlic plasma clearance. Similarly', ··d t'a r,u K,'l.· I,,· ewn-uon of d m !.: " in the- kitllll'p would lit, n -nal ('«ni 0I)' pla,,"l.J clearance. III p rdl1in ·. tilt' te rm I" II-"'Ul is tln 'l ~""l:1. a.. pla..ma is Iht· common sitt· of lIwa..u re nx-ut . In atklitioll. n Ut' o fll-n drop-, "u1tJJt"ic Of n:cn101"J wl lt'u d t'StTih iul!: clearance I,,· ti lt' li\"t'f ami kKlnt.,." . n "Spt"l'· tin,I) . I",'eall \(' tilt.,..· pnw:t"Sst"S ~(' nt'rd ll)' occur in tilt.,.., rt"Spt"l1i\1' 0TRans . lI owt,,\"(' r, 1I1t"lal-oul i..m tk","S Ut'Ctlr in ti M' kidnt"\'S, a mi e xcn-non (i llio hilt ' ) IItW"S 1"""lf in tI.., li\l 'r . 11M'Wfu n ', till' ",',,,u lllpliun.. 1IIldl'rl)in~ tla- d t'a rdlK't' IlUIllt"lll-iatu n ' fUf a spt ·d fit· Ilm~ ..ho nld alw1l)' hl:' flut ...tiollt.. J.
..
P10sma Versus Bktod
d"a"'' I""'-
OtarOlK1
FUf IIl;1n) ••p p lkllt's til t'stilllalt' t'\Iml1inll ratio, om- 1It "t.. L.. to l"OI1 \1:"rt t hi.. dc'ar.lItl't' \ 1J m ' lJ;l'i.t..10 11 dm!/: ('t ill · l't ' nl ml ioll ill p l'l""''' tn 1II1t,I);'l'i.t"t:1u n III(' ll l1ll't·lItr.ttiu n in bInIIll. ll1i.. l"lUi\"l:'rsin n i.. a('('IJIlIpH, llc.. II ))' C'\11lII'""\(,lItall)' dl 'h' nllilli ll~ tilt' hl'Il",I-ftt-pl,t.."", t."lJlll't·" tra lio ll rollio. S inl'1', I,)" dl:·fillitio ll. tilt' prtllllll1S of tilt' f('!ipt'l1in' dl:·ar.tIIt.'t' an d {"lJlll't' IItralioll It'n ns, h .l'it"t:1 011 IIW;tSlIrt'lIIt'lIls in h lntlll a nd pl;lsllla . a rt' ("tilial to lilt' ralt' of l:'lilllillalion. it follows tlrat : Plasma clearance Blood clearance
Blood concentrotion (C,J Plasma coocen ITotion fC)
5
11 lc' (lI l1('I'lIt m tio n mt iu is a fum1inll o f tilt' IWlllatot.-rit alll i of tht, hill(lin~ o f dnl ~ 10 IIlJt" ph"lIlit pmtt'ill.. ami h llIlJtIt.'t,IIt."lJlllpolll'nh. 111t' n ·l;ttio mhill is tlt'ri \t ..1 in App,·ndi\ 1-(:. St nm~ hill(l in~ tn p l;l\llIa p m h-ins p n lllu('t'S a mlio 1l:'Ss t1..m 1.0 " it " :1 IOWN lim it o f ( l -hl:' rnalnl'rit ), wllt'll dnJ~ is n~trit.11 ..1to p la,,,,,,_\\1M'n h;lIdill ~ tn h lllllli t't'll.. i.. ('\h'ns;\l', till:' rotlin IJldy ht, mud l Jl;n 'alt.' r tlra n l.fl,
Additivity of
OeorOIKI
111t' all aturn~' nf till:' IU"'I ,UI I w Jt ~· Ilil1ah-s th at till:' dt'ar.Ull'1' of a dn l~ I,)' UlIt' 0TRall at ltL, tn d ,·ar-uK't· o f ;tun tlWf. Thi.. is a t"l1ll'it'fjllt'IK't" of th t' dmlLatioll. ('Alllsidc'r, for ('ump ll', a ll nllt Ih al i.. d imi ll;llt...1 I,, · lJolh n 'n;tl ('x(n 'l in n dlltl hl:"P',til' lIll:ialll, lism . 111t'n
16 1
CHAPTER 11
Rate of Rare of Rare of elimination = reno! excretion + nepatic metaboli sm
6
Di\itlillg, tlu- mh' of n-mcval a...so<-iall-t l "'ilia ('m,.-II p mc't:'ss hy the illl"llll1ing, dnJ~ coucentration (hlood nr plasma ], whidl for hot h orga ns is tilt" same (C ), gin 'S tilt" clearance a.ssotiah-t1 with that pro{"l'ss: Rate 01 elimination
C
Role of renal excretion
=,,-,;:,== + c
Rare of hepatic metabol ism
C
7 T0101
Renal Hepatic clearance - clearance + clearance
Thus. total ch-arance is the Slllll of tilt' clearance s hy each of tilt" diminating organs, " ('{'all"!' of lilt' atltlithi t)' o f d earalll,(', tilt' n 'lath":' contnbuuon of an~' o~an to drug cluninunon is readily m l{'ulah'll. Fo r ('.'(;Impl(', tln- Fract ion of drug exert-ted unchanged (t!esig,nah-t1./i', SI.'1' Chap. 3 ), "l'i n~ tilt' frd{1inn of total elimination that 1M."l.' ur; via n-nal cxcreuon . is jus t renal clearance d i\idt'(l hy total clearance. Dill' exceptiou to lilt" addithit)' of d eard ll{1:' is pUlmOllil!)' clearance. This is din- ill part to til(' blulxl sllpply to tin' IUIIg,s Ix-iug in series. r ather than in parallel. with ot her o~ans of r-lunnuuion ;tlld in part to tilt' total cardiac output p'Lo;sing thron gll tjn- lun gs lx-Fonn·adling till' sill' of 1l\1"lO;Un'I!Wnt, usually h lolXI in a peripheral vein. TIlt' ccucentranou m(';t\ tlH'{l is that It'a\i tl ~, rat her than ('ntl'rillg, til(-' lungs. TIlt' lise of thi s concent ration to ( H,Ill-lI lah' d l'alallt1 · is in("l)llsish'llt wit h its ddinition {see E'I ' 3 ), Indeed, if thl' pulmowl!)· extructi ou mtio is h i ~h , cleurancc vahlt's {';l lclllat('d in tlw usualmanner lIlay ("'l:'11 ('xl1't'{1 ca rdiac output. Illakill~ interpretation problematic. Cll'ar..l1ll"l's of dmgs by the- her-r am i till' kid lll")'S an' now cx armned. Each o~all has SIIl"l.1a1 auatonuc
HEPATIC ClIARANC! Althou gh dm~ lIwtal Mllism
( H,I 1l
takt, plal"l' in lIlany
0 'l!:.IIlS ,
till' lin 'r fn '(lllt"utly II
~n'all-sl mdalMllil' (~olll
most di n -ct
blood clearance '"
0H Hepatic
blood Row
' EH Hepatic extraction ratio
II N ( ' VII is tilt' sum nf hepatic portal and h('Il
8
a\"t' m~1'
Perfusion, Protein Binding, ami Enzyme Activity T ill' fol1 U\\in ~ priuciples, rt'l ati n~ ehall~('s in clearance- and extruetion ratio to llltemtinm ill j'lI'rfllsioll, ploLSIlI
non.
'.2
' ' ' ' 'OON
CHAPTU 11
P..· rfu..ion. At I,·,t>;l fi,,· pnll'l'SSt's.;I.>; shos vu in Fi ~. 11-2, lIIay afTt·c:1 tht' ahility of th t· dnl ~ fmm blood . I! uwt"vt' r. wlu-u ti lt" Iwpal k c·.\ tmetjnn ratio app ruad ll's 1.0, tilt' drug must haw !lild suflicit' nl tune whilc' in the her-r to partilioll out o f tilt" blood {'(·II. di sso d .lh · fmmillt' pl,lSlIlil pmll'i n. !liLSS I hm ll ~ l til(' h l'Il;ltic meuibnnu-s. a mi lit, dllier metabolized by a ll ('1l Z)1 11t' or transported into the hill'. or beth. AI...o hluod dC'afiUl l'l'
hver In ext ract
a ppn);ll·h,·s it s madmum value, hll );ll i<-' h lo ud flow. U nder t his co nd itio n . dim illa tio ll ts
rate-limited by pe-rfusion and 110t by the spl't"tl o f any of tln- p n ll'( ' Sst' S dr-pict ed in Fi ~. 11- 2. Ch:mg:,'S in blo od How pmd lll't· co rn-spondtug d lanp;t·<; i ll l'!l';lralll, ' and nih- o f elimination. hut llil' ext raction ratio is virtual! v unaffected . III cont rast. elimi natio n o f a t1nl~ \\i t" a Inw ('.'l llllt'w !ll'n' t"IS(, in ti lt· on-mil Sd lClIlt" (Fi ~. 11- 2). \\11('11 the t'x1md ioll rat in of It d m R is low, Illl' \'('1I0US d m K comvntra nou is \i rt llall~' id,'ntil';al "illl lilt' artertalconc-ntranou. hy defin ition. Therefore. dla ll~l'S in hloo,1 f10....should produce 110 d l,lUKl' in lilt' dnlKcoucentratton \\ithill tltt' u!"K" II, ill mh" o f (,limillatioll
nil:. 11- 2. Dn 'l: ill hIo••1 i. IU II..l tn Ill
Q
(1"""'."
11); I"M
(1" t"l lnlo II..· ""1""'1'''"" ", WiThin tI,,· I..·· p"'Ijt..1....II" Iur11. ·r 1....m. rOn llahon ,
Blood
a Unbound b Bound ~ .=;:- 0r~cg -=== Drug 'I
Hepatocyte
Unbound ~ Metabolite Drug ..
Bile
Lidocaine
15
Colloidal Chromic Phosphate
'2
~
)
•
10
§. ~
u c
e
1 u
5
--- . •
0 0
• Antipyrine
10 Hepatic PerfusateFlow (mLJmin)
20
. '11/:. 11-3. ( :m" I.." il.. .J..III .a.." ,i"l/; Ih..1 II. · .. ·,,';t,, ;t~· "r II..· <·Io.·;or..r.. ~· "r .. l"" u," M" .. l t" d ,..r,!t,,,, In h~ ••1110 , \\, ,,.,, M.t n.d i".. r.d i" h u, n wid, 1I" lil'yri ll" d.-anu .. o· ' ' lU.. 1i, .. I., " ·lI ' 511'l~')!)'j. 1\;l.'l6.) .~.
i.'.
Ii"",.
Ii"", ...
163
ELlfI.',lNATlON
(l-WTEP 1 1
or hy d(,fjnilioll in dl'ar ,lIIl,(', From Ell_S, hm\'t'w r, it is M't'll tha t th(' he ll;l!ie ext raction ratio vu ru-s illH'rM" ly \\i lh hlood UIl\\' wlu-n l'!('a nlll{'(' is constant. 111t' S(' expect attons 1"1' ~an li ll~ jll'r fusioll for d nl j,ts of hij,th ami low ext raction ra tios lift' iIIustmtt'tl ill F i~. 11 """,,1 . Bl'p n 'S('ntatiw d nl ~s and 1I1daholih' s \\i lh low (It'SS thun 0.3 ), illtt'nllt'tlhlt(· (0 .3 10 0 ,7 ), and h i ~h (!-:n 'a!t' r Iha n n.7 ) ('\lnu.1 ioll ratios in tilt' llvcr an ' lislt'tl in T nbk- 11- 2, :\ wenl of cautiou is T1t't'tlt'tl hen ', :\hh()u ~" mass-bala nce pnlldplt's sta tt' Ihat d l;U1~t'S in blood lIuw an ' !lut expect ed to alft'r lilt' l'!('amn('(' o f dr ugs of low extraction rat io, t111'n' art' ph~-si llll ~~k lIlt,(..l.anisllls thai llIay St,(1 )l\(laril~' p roduce such an ('fT('(i:. Examples ,m ' thl ' pn ',"'ll(1' of hmTlt'tJstatie cont r olmec hanisms and a IlI'rfllsion .lillli h'tl supply u f cofactors such as O\) "J,!;t'lI or sulfate. Bindi ng WUhin Olond , For a d nt~ with a lugh t'xlm<1ioll rat io, lilt" li\"t'r is d t"llrly (~Ipahlt' of fl'lIlminl: ,JI tilt' tlntg Pfl-st'IlIt'l1to it ill spite of hilltlillj,t to blood cells ami 10 ph..nM proteins. Haft' of t'li lllilla!ioll de-pends Oil tot al concentratiuu in hloud , Ct' rtainly, a dt'l·nw.t ' in binding aids in n 'll1o\ing a dmg; hut ill this <'a.\I.' , it is cSM'lltia lly all n-mocr-d auvwav. T hen-Ion- Ilt'itllt'r t'xtmli:ioll ratio nor dt'a nUil't' is man-ria llv afTt"l1('t! hv d l;lIIgt'S • . in 'h i ll~l i ll g. Fur a d mg \\i th a low extracti on r atio, clearance tlt'llI'ml s Oil plasma prote-in hilltlill,i: hl't.·all"l' only unlllJIIlld d mg 1'II ' I ]('t ralt'~ membranes and is available fo r elimination and 111.'1',11 1"1' 1111' limp iii t1 m g ('tllll't'lllmtioll ,K' n JOiS tht' [ivr-r is small. The 1I1llll.JIIlHi coucent rution ill plasma Il'a\ill j,t 111I' liver is almos t Idr-ntfca l to that ill the ein1 11ating p la...mn. Cu . Then the mit' o f d rug t'li minatioll ill tht' !iw'r is tlin'l1ly n-lated to tilt' concentra tion of dmg 1l 1l1II. llluti ill 111I' ctrculatillg plasma. ,'\(-u m lill!-:Iy,
Role 01 elimination -
CLu Clearance bcsed on unbound concentration
Cu Unbound concentration.
_1 b:tr.ctI_
T.It•• 11.2. Hepetlc M . .....n....
epre
~O" i "
O~,,,od ne C~"
No<':llpl'J!,roe
Amol
Am,!o
"""'*' Cefa1:oI.1'l
Cvrenove Cephak:>tr.,,,
C,proI\o>cOCll'l
~o" 'od''>e
""""'"
FUI'~de
Genlomi(;in
Llmi.",..
Tel!ocyd,ne
9
_
0-,
...
Cl-W'Tt R 11
' 64
E\lm· , ..ill~ till' rail' IIf Ilt' p"ll k- t'limillOlholl n·laliw· In till" plasma ("1I11('t' nlmfillll. it h il.p. pan'ut lll,,1 tl.t' IW!'J;lti l' p la\IIl
Hepatic: cleara nce -
fu
CLu
Clearance bc sed on
Frodioo in plasma unbound
unbouod
10
concentrotion
For ('\ampl,,, if/II \'aril"S l:\\ufll ili . '\01:) d Ol'S h(' I);Il ic {:k-arann '; tiM' IIII,"OUIIII d l'arAIK"I' n.·IlWII.'i 1IIll :llallJ,:I't1.
TIll ' ~ 1.lt;1 in Fi ~. 11-1 oh l ailH.'c.I in tht' isolalt'tl. pt ,rfu\l:"(1 rat lin'r. iIIu"'rah' ,lit' points liMIt.:· "ho w . In ,I.i.. preparat jou . prrxein hilJ(lin~ can l)t° n'adi~' alIN\'(II",· dl.an~n~ liM' (ull('1'n l ml ic lIl uf tl tt· hil KLn ~ pml t"in. and pt·rfU.'iioll can be Ilt"kl (·(In..tanl . \A IIl"itlt' r fin! lolhul.nlJitk ', a d nl~ o f kM' ( '\tr M1ioll ( "\ 1.'11 ill tIlt.' al"" 'IK'l.' o r hillllill ~ ifll - 1.0 ). As l "· pt 'til"ll. tht' (·\tr.K1icm mHo (ClIKI d.-ar.ll K"t") o f tolhutami(k- is di rt't.11~· p mportimliJ to
Ill.
Propranolol
1.0
Diazepam o
~
Phenytoin
is 0.5
J Tolbutamide
o
o
0.5
1.0
Fraction Unbound
.'ll;.
m.·...'
11-4 . ( ;'''''1.'''''''' ,b llt. • 4ot;li'lt..1ill ," , I"' ..ItI....l. llt·rf" ......I .... IIi -.. , . " .......; "lt ll...lll... "'·n.il "1 1~· ..f llt-patic' ..... r;ll1;.." . ..u" t.. d ,,\CI" In frood ' "f (Ino~ un l " ..1';Inc .. , Ell r;ll1M"'I'lIIM. I'I'" '1".r1M,md I" fr;M1i.." .. "1 ,,..1 ""I~' .. ....." Ih.· 1...' ....u" , 11.. , 1' ''''r tl..· " nhn' n"",,· "f t.ir..I"' J: fur 1,.11..,1,"" "", (T f 1..11 ~' ,"'.• It 1i""I,...1 "",,,. fll' ,Ii""' ,,,,,,, I.: .." ,I 1 ·"~1l1in (.'. \\1..." tI,,· .·'1.....11<'" r"'i" i. " ,"',. _ ,.., .. ,n .. ,.t. 1>I "'''~1' ''" ..,,.lr..h' '', . In ,,-hod, ' fr;ll1I<'" ""lu"..1,. ,·..,......1'"'''' It ..;, ... nu,l('I ' ~ ' lif~;,,1/, 11..- (,,, " ,lralll,,, ..f "".,m in. II ,.. linl!, I'"".-In. • ,In,l!, ...... 10. · .·I " lo,....1 fn ..n ,......"I hi""I "I · l r;M1..",- n .... " ".11,,, n· d Tt '0;' '~"" . (I ) "'" .J",r 1 1 fnn,, : 11 " 1' ..II-!\I"',..I. U C:.. C. " I ", . R.II 1 Wil~im..n . ( : ft.: 1·..rf".it ·I" nilo..J .,.{Tn 1. "I l>l.t, ,, ,Inolo: I,;,...."l!,.~, 1"1""1;'- ••..1_1....' . uf.· SU.• 111:1 2.\--1.-'1. 1Q7fi: Di...p''' I-- H.c ... -t.....I. M . ' '' 'lId. . u .. ~....."U1~ <: . ..,..I !\1I1l11.. Ii .: !'n"r in 1..,tt1'I("'od h.1""'",. d.·;oant..·: U...(Tin,i "..h'"' I..~, " 1. , ,{ I" ,,,,, ir.· t·. ·ar..' · "'11, ,I.......,"'tn. • •In'll: .,{ l>ilo1t inlrin....· dr..n.o.. ~. ill , .... iKtl.cl•...t. l"·rf"......J ..... I" I..........,.,.liun. J, 11....., oL,..1 B.. ,>I","".. '21~ · 1 -li". I 'M _ TolI..rt... nioJ..-s.... W.lH.c ... L.ntI. M : I,",,<'i" ".",lin" ....,II..,"" · aI...." ~h..tin ", tI, 1",'h" llltnidr. a tint( "j 11... inl rin in II... "'tl.cl..... prrf" ......J nI It.... r ,...,....'"' " 11"'",......&.in . 8 io 'ph........ I I :tz\--W . 19'i3. Pn'l .w_ J" '" lU I . Chi'llt- M ,~ .. S.....n .
... ,w., "....,
...r:-.
....... ..l Ii..\ od \ 1",,,, ,. n J : \ twn."'·p""n" ......,...... it. noll .. P""'"I",ul" f,...... ;,1 1"1"'11(' ..h'"i'llll i h,lo1t~ 1...., 1 n""I" k .\ .11..1\ "j >1 ,M'uu.......'" tJ;.. II...... .t.....t. p.-n"....J ..... 11-..,., Il.,....t< >&::!'·•
.5 .'§!J1l-,'>Y.1 , I\t>r.'!> I
pn,.........
CHAPIH 11
'65
ElM NATI()N
TIll' llhsl"",ltinns with di :v,l' jl;\IU an - ill ll lll i nllti n~. 111l' extraction r atln (am i d ea nlllt,.·) [r om a \ .11111' d OM' 10 I.U (ill till' absence of bimling,frt "" 1.0) 10 one d ose 10 zcm 0 11 d ( "'n'; Nn~ till' fnl(1ioll unbound. C ll·;n ly, pllltt'i n hilld ill ~ ca n limit extraction if hintlill~ is high l' llImgh. Howev er, tllis snnatton is lJolip hysiol~e ill th ai tilt' fraction unbound is vilrit'(l llt·tWt't·1l I .U and 0.05 . a 2()..fold ehangt'. III practice , a t1m'(·fold d mllgl' in [u wnuld lit· l,msitlNt'tl pa rt it111arly b~l' for a drug bound to album in. UIIlIt>r IIll'M' mort" n-stncn-d n mditions. till' l'~I It '(-'ft't l n-lanous hip between d l'anlll('c am i/ II holds. 11111s. for diuZl·jla lll. iu tilt" rt1-.';o n when- extract ion mtio is low (I1}\\'fi,). clea rance is din-ctly pmlxlrtionaI to fit. At till' otlll'r r-xtn-nu-, in till' rt'¢OIl wllt' rt· tln- l'xtmdinn m tio is high. d (';lnul ('(' \ is d laml'kristi<.' of metabolism II)-' a ¢n'lI t'UZ)'IllI' both ill d tm am i ill I'lw. The hl'h adur tlisplay('(I, typic....1 of ~ 1it'hat·l i s ·M {' n h· 1l kint'ties if tIlt' all" p mad l toward till' maximum rate. \ 'm, follnws th t' rela tion ship. dl<\1l ~l'S
I".
. Vm ' Cu Role of melobo ll$m ., K C m + "
II
ill whtch 1\.11/ is a constant, till' ~lidlat'l i s· ~ l enlen constant . In 1;" 111:)111(' kim-tics tlu- m llli' u f \ '1Il is d in'(·tly p rupu rtillllal to ti ll' total concentr ation o f en zyme, an ti Km is an inverse fUlld ion of the affin ity IM'tWt'l' n dmg and 1'1lZ)1I1<'. :'\ot t"in F.fl' I I that a value o f ell t"fPI
12
Its " 11m' dt't.' n ·;L'it'S at t1 nl ~ l1l11t'C' utmtiollS app madli ll~ alld l'Xl,( 't'tlin ~ till' " lhlt" of 1\.1/1 . Th is is shO\\1\ in the' lo\nor part o f Fi ~ , 11--5. S ote Ihat the hiJ.,1fll'st d l'anllll't" is tile' mtio \ '". / KIII . a \tl. Tk,(~
CHAPTH I I
'66
Vm
Rate of
Hepatic
Vm
2
Metabolism . i,;.II-5. \\l,,'n I", >;ol k mo1:4I....i~m r,,j~ "" .. \ h :h...·lis· M,""h·!l "'in<"fi<.~. tho· rah' tlf m..t"I. .. 1l\l1l ill("ft·;a.. .-s (" 'I' 1o:r.'1,h ) ,,,wlInl a Ul<W mlllll tIlt- pla' m;,. ,11"11: (''' ll, 'ul r..liu ll i. Incn-ased. n ..· (uK't'nlr.. tiu ll " I ",hid, .I..· rAil ' i. < ~h;lK't'n troltio..u . n ..,......, ..,Irollk ,,, at ·Md , tl..• clo·ar,uK't· i ' tlllt··luI ( tI...
Unbound Plasma Drug Concentration
,ll!,....
a1... tl.., IV" \01.1 ,.... The
fur II..· " ·JoIlie" "I,i,"
art'
Vm-Cu Km. Cu
Km
,,,t,,.,, \ '''1, ...'
m.n i ll lllm i.
Rate =
Vm!Km
''fl' '''litl'n
,I" ....~, _
Hepatic Unbound
Unbound
Vm
Clearance = Km + Cu
Metabolic Clearance
Km Un bound Plasma Drug Concentration p.orfUSiHII, p la.~lIl a p rotein h ill(lilJ~. ami .·1IZ)"1I1(> act ivity ;!n' aln-n-d. Om- of IIIt'M' llllMlds. the 1t,'('ll·,dirn.,,1 "u)l/d , in wl.i(-h instant aneous andcompb-n- lIli.x i n~ occurs withi n lilt' li\'t 'r,
is part it'u larly attractive because it m il « 'atl ily II('
t1l('S(' pn ncipk-s. Even to p n '1.lid: th uS(' siluations ill whlch eitl l('r clearance or t·xtr.l(1iOIl ratio is " fft"{1('1.1 allli ti lt' ('.xp('(1('1.1 drrccnou o f t:ha ll~(" TII(' well-stirredmodel states th ai 11.\ ('1;1 to SIl Ill Ill'U 17.('
t holl~h it lila)' 110111(' qua ntitat ive, til(' model allo w s
QH • Q H -+
OIll'
/vb . Cl;nt
fUb ' Cl;nt
13
when- Q'I is ti lt' Ilt'patie hll. MI fill \\'; C/,,,,. is tln- tntrtnslc d ear.ul('(· that n-lates rute of metabolism to unboun d concentration ut the ('111.)'1111" silt·, illltifi l/t is the- fml'lio ll unbound in hlood. '01(" hepatic extract ion ratio, CI' b." IQII' i.~ then 14
TIlt'S(" 1\\11 equations haw tilt' desln-d p m pt,rtit's at tilt' limit s. Thus. wln-u 1':" app rnadws 1.0 (tilt' pe-rfusjon mh··li mitt'(l l"omlitil)n ),fi'/t ' C/ " ". is mu ch ~n·ith· r tha n Qu,
CHAPTER 11
ElMNATI()N
,.,
and l'!t'ar.ll1('l;' upproacln-s Q" (Eq. 13). Changes in
Cl~,." a ndjil hen ' art' lJOI I'xlx't1{'(1 to illllllt'!lt"-' CI./1 and Elf much. Conversely. when EJI is small. Qu mu st I ~' muc..h great er than jill> • Cl~"" . :-':uw E" a nd CI."J! a n- approxinuued hy jill. . Cl~,..IQI/ a nd fill, . C1...... n.'Spt't1i\l'ly: lilt' \ 0 .;). Suppo se, e .g.• that tln- he patocellular activity (jnlrinsil· dt'arallw ) varK'(l t'vt'nly from 0 .01 10 100 U m in allloll~ a Illfl{e ~mp of ccm pounds. i.e-.. OW'f a IO.CX)()-fold mn~t' , am i tha i none is bound in plasma Ifut. m: !.O).l1lt'1l slIhsl ilnt ioll of Illt'se vulues inlo E'I . 14 shows tha t only those drugs wtt h an lutrt uslc ch-ar,lUt" in lilt' narrow r.1II~" of OA3 . QII 10 2.3 . QII ha\"(' an mte mn-diate extraction r atio. l.e. v" ItIl'S l~otwt" 11 11.3 alld 0 .;. Stril1 ly. iLS whole hlt ~~1 t1t'liw'~ d nl~ 10 Ihe llvcr. Ihe Iracti on uubouud ill Eqs. 13 ,Iml 14 should n..fer to Ihat ill blolMl nnt pt l.s ll1a. For tlitlal1ic- pU'lx)s("S, hll\\"("\'Cf, here and t hmll~"o llt n-maimh-r of tilt' lXIl)k ..... lu-n- Eqs. 13 and 14 are applied . the two terms are t'(luis-alt'nt. A major d iS(·n o'lillll·" IX"(.llrs when till' blood -to-plasm a concentration ratiu is mudl grt'all'f than I.
To n 'ill: h lilt' ~I'li(' r.a1 circulation, a t1 m~ ~'''-' n orally mu st ! liI.\ S thmllF;h Ihe liver ' ia tilt" po rtal "plt'm. The fr.K1ioll ('s('wdpi ll~ ehuunation b~' tlu- hwr. F". is till" IIppt'r Iimil of tilt' oml hitlilvailahlli !y. It may I ~· calculated from tht, IlI'patk extraction mho, Ell' Shl(" Maximum Olol bioo voilobility - I - Hepatic extraction ecnc
15
Hepatic edmt1 ion rallo run lx' (...tlma !I'(1if tlu· lu·'lillil- (bllllxl) clearance and Iwpatie blood 1I0w an' known o r can bt' approdmated. For iIIl1slmtin' Pll'lX>St°S, (,m"ldt'f tilt' folltl\\i ll ~ dat a ohtaillt'(l afu-r an tutraveuous (i.v.) clos e (seX) III~ ) of a d m g: C lIlIlulatin ' 1lI1101ln! excreted unchanged (.4.1',.) "" 15:2 m~, ACe :: 3."1.5 mg-min/ l.. and tln- blood-to-plasma concen tration ratjo (e ,I C) = 1.:2. Extrarenal t'!imi nation Is il.SSll lllt'(l to occur onlv in the livef. l1lt' d t'a mlll'l' ( D f)S{"IA VC) is then 1.3 L'min. and the hlood clearance (C U (C1/ C )] Is I.Q.S IJ mill. l1lt"fr.t{1iolll'l{'rt,tt-d lIndliUl~('(1 (AI'''; !>n".. ) is 0 .,104. Af1, m lingly. th t, (('11;11 "l f ll ~1 d l";lr.lllf'l' (fl· , C I .t ) is 0 ..12 l i m in. a m i hy d ilTt,rt'II("-'. tilt' 1lt'(l'ltiCblfll)(! clearance [( I - fe )C I .,,] is 0.;6 [J min. Di \itlin~ h~· hepanc hlood 10 ohlai n tilt" Ilt'(l'llk extraction ratio. the maximum oral bioa\
",1\\.
16
which. in th i" example, is 0.56 for a hepatic blood f1nw of 1.3.'5 lzuun. Bt'in g p hpiol'l¢lwdlly dt'h'nnim,1. 1111 amount of phunueceuncalmanipulation cau Imp ro\1.' 011 this value fnr an oml dosa gt' forlllulation . AllY dm~ \\i I1l a hl~h ht"lliltic t"Xtr.l(1ion mtio (s("e Tabl e 11- 2) hilS a Inw oral hi t );l\';u lahi lit~, . 111('fl" may lit.' Otlll' f fal10rs Ihat limit dmg: n 'ac hillg: till' portal \l'i n and so fu rtlw r tlt'l'fl'll.'i(' h itKl\
111t, .. lTt"(.is of dlall~ n);( h lotlll 1I0w , intrinsic dt'aran l'i.'. or protein bintling: on nrs l·pa.'is t's:tmdinll ('ml hI' prt'(!idt'(! using: lilt" u:ell.stirretl m()(If'1 hy sll hstit ll ti n~ Elf . 14 inl o tht' fl·lalioIlShip"'lI = I - f;,I. 11la t is,
.
,
EI>'v\INAT'ON
C HAPTEi 11
17
"'/1
II shou ld Ill' re-e-mphasi...t"(l lh
hy 1I slIffide lllly l a~l' factor (F ig. I I- JJ. 111t' principh-s lu-re n-fi-r to tlu ' n ']atin ' ft 'll dell(:ic's ti M! 1II11(It'si dla"~t"S in tln-S(' Iacto rs an' likd y to produce. 111l' d Tt'l1 011 first-pass extrac t ion c..til also Ill' ,;suali7.l'tl hy rt'~ardillg perfuslon and protein himlill~ to he ill t"I llllpt"tit io l\ \\; 111 ('Il Z)lnalic al'l i\ity: pt:rfmiu ll alltl prote-in hi1ltlill ~ help 10 1Il0,,,' dmg lhn lllgh til(' onsm. maktng drug avuilabh- In til(' gt'Ill'ml circulation. WIWrt';lS t'1IZ)l llt' ;u;·ti, i ty n'moves tl m~ fmm till' l)I'rfu si n~ hlood. Conside r first tile case uf a dm~ wnh an Elf near ..w m. tllal is, Q" Illudl ~rt'Olh' r than fill, ' Cl' i'''' 1111'1l 1'"" is indl 'pl'mll'lll of l'l liIlI ~t'S ill Q" , C L ,n, or fill,' This is nul S U T'p ri.\i n~ a\ till' extraction is so small that t'n' !)1 h i ll~ presented ~t'ts P;l\t till' llct-r ,U\~".ty , Consider Ill'XI till' t"u nd ilioll in whil'lIjill, ' CT."" is nmdl ~rt'illt' r than QII' so thOlt E" approaclu-s l .n. In thi s case. 1'" ... Q,/ (jiII, . CT,,,,, ), thai is, hio;l\.tilahility is low am i d(,pt' lId('nl on all IIm't' factors. An illt'n';l\(' ill blood fluw inn l',l\('S hiu;t\"ai labil ity b~' dl'(: rt';l\ i ll~ Iht, lim e t1m ~ spt'm ls ill Ihl' lin 'T', when- t'!illlillalion Ot't·UI'S. An inert-a.\(' ill t'il llt'r ('1I0·tllOlIi<: activi ty or in f ill, (whid l nuses lilt' unbound couceut ration fo r a ~'l'll i lll,(Jlll in~ total (u lIl't' lilmtiou ) dl'<.'rt';l\('S h io.a \"ailahi lity hy int'f'(';L, i ll~ 1!It' r.th · o f eliminanou for a Wn 'll mit ' of pn-seutauon In lilt' live r.
Biliary buelion and Enltrohepalk
c
(Bile Rowl . (Concentration in bile) (CancenlJotion in plasma)
18
Hile flow is a rt'lllli\"e ly sh ·;u;ly 0 .5 to OB mlJmill. Thus, for a dnl~ with a n m(1·IlIr.ltioll ill th(' hilt' 1"tIIl,t1 10 or It'Ss th an th at ill p l;l\ma. tilt' bili;!!)' dl'amm..., is small. A t1ml-: that ('Oll('t'ntra h's in tilt' hil(·. !Iowt·wr. Illa~' haw a rt·lali\"('ly h i ~h hiliar)"d(·ar.lTIt1' . Inll('t'tl. the bilt·.t().ph~lIla l"tJlK,'nt mlion mt in (. 11I appm;ldl IOIXI. 11It'n ·fon ' . bilia!)' d t'ar;Ult'('s u fSoo m l /min or hi~t.t·r l'all he al'iJit...·I'll. En 'lllllally, of (1)\1N', h iliary dear,lIll1' is lim itt't l by Ilt'pa li{' (It.·rfu sioll . Bil(· is not a pmd lll'l of filtmti oll. hilt mtlU'r of St·c:rt·tioll o f Ili!1' at'i(l, ami otllt'r stlluh·s. nIt· p ll of bilc' ll\"l.·m~l·s alltltll 7.4 . 111l' bilia!) ' Inlll slXIt1 of dnJ~s, !Juwl...l ·r. is similar 10 lu;1i\"(' Sl'Cretioll in tilt· kidllt")"S (p . 172 ) ill tilat it Illay 11l·(' llIlpt ·til i\"('I~.. illh ihih't l. A f(,,\\-, ~(· I l(' r.t1 i ....a lions t~.Ul ht, lI1;ul(, n-gaf'(l in~ th t· (,ham{1l' ri\ lil'S nf a dnt~ m '(,II'(l to 1· 1l.~urt· ll i ~h bilhl!)' dl'amll l1', F ir,;t. IIII'
ELMINATlON
c t-t.\.PTH 11
'69
Int'l:hanisms t'~i st for ad ds, ba ses, nnd un-lon br-d compounds. SI'l-'(JIJ(I, it IllIISt he polar, and, last. its molecular wt' i~h t must exceed 250 Winnie, 111l' latt e r two requirements may 1)('
RENAL ClIARANCI \ \1 11'T1 tilt' ran- of urinary excretion is dt rectly proportion al to the plasma dmg couceutralion .
Rote 01 excretion • Cl II • C n-nal clearance is constant. Thi s constancy forms th e
b;l~i s
19 for th e use o f urine data to
determine tl.l· lim e course of a dmg ill the bod)' (C hap . 3 ). Iuterp n -tation o f uri ne Lllt0<;,(' and T inu- Dependencies ), plasma protein binding, uri ne fl ow. am i urine I' ll . How thes e Factors illllut'I1{"(' n -nal clearance is explained by the 'U1atomy am i pll)'Si(}I~· o f th e
kidnevs.
The Nephron: Anatomy and fundion 1111' basic ana to mic un it of n-eal funct ion is tilt' nephron (Fig. II-i). Basic l 'OIllPOlll'lII S a rt" tlu- ~1(J llIt'ml us, p roximal tubule , h lp of Henle, d istal tubule, ami (.'OIt{"(1: i ll~ tubule . 111l' ~loll1e m l m receives hlood 6rst and filters abo ut 120 m L of plasm a water each mtnute. 1111' filtran - P
Portal Vei n
, @
Liver
,, ,,
@ , I
Bile
,, ,
@-----@ Elim ination of Drug and Metabolite
Intestine
Flit. II ~. \\ "h<-n a (In'l( Ill) j, aI"",>rilfod (",'n inlr-rl......J (",m inl,.,.r i'll·, u has lltKIc·rxun.- ..nl..n.l"'-p;&lk l.,T1inlt (,,*......1 lUTl l. .. .. ..,,1"....·"1 u { ,h_lril"'lk"" SimiLr.ri).', .. t n a droR is mnwrt....t to .. " 1;01.>Iii.. ( M) thai I. W'crf'I", 1In h iI.-, <"0 " ,...11... 1b ·I. tn drul( in tho.- Inl ...li...., ", 1 dn' l: i, n·..h.o rf.....1 (da., lll..l . m"'.. 1. II..•dOOR I "'..) UlKk·f'Io:'''.... ,·n· trrut"'P"lk t)t1inK, in It.b ("' irKI;",,1~ ' tlm",!tf, a mt1a1".Iil('.
CHAol'lU 11
110
1('01\\-' tIll' kidneys as urtuc. O il ]ea\; ng lilt' glomerulu s. rlu- SOIllU' 111000:1 p t · rfU stOS both p mxinml and d istal po rt ions o f tilt' tubule lh n mgh a w rit'S of inh'rt''Onm'<.1ing d l,U1I1C'k Aplll-'ar.Ul<" · of dmg in tilt" urine is th..• Ill'! n-sult of filtrattou. S(-'o:: rt' IiUII , illld n-absorptton, 11,(' firs t h m p n )(.'(' Sst-'S add d m g to tht· p roximal part o f 11ll' IUIllt' 1I of tl l(' I\eph n m; tIll' last pro(,.ss Involves till' movement of d m g (mill th..• lumen luck into tlu- bloodstn-am . 111t' exen-tkiu mil' is, t1wrt'(on-',
Rote 01 _ I _ F [ Rote 01 Excretion
I
RI
Role of
Filtration + Secretion
I
20
when- FA is tlu- fr action reabsorbed fm m the 11I1IIl'1I. A schematic n-p resentatiou uf Iht'S(' pn M:'t'SS(:'s andtheir approximate location in till' ne phron art' gi\"t'll in Fig. II ...';. 1...·1 us loo k li t eac h p n ll't'Ss in 11In! .
Glomerular Filtrcrtion App mximately 20 to 25% o r ca rdiac outp ut. or 1.1 L or h lucxl P" minute ~cx's to till' kidneys. or this volume. about 10% is filtered at tilt, ~lo lllt' n1 l ns. Small molecules (moh-oular weigbt les s than 21)()O Wlllole) pa-...s t1m m~h tln- sk'\"t· with ease. and ('\ "(' U for smal l p mlt'ins SIl('il a.'; insulin unr] my{)~lolm lin , tln- nlt rafiltrate (.. mcent r auou is doS(' 10 Ihat in
Glomerulus Proximal Tubule
Venous Return ."'"...~
<,
l oop 01 »> Henle
.'Jl:.
,,,,w,,,,,,.
11_1. n ..· fund"' .....! ;u, llfi;l!mni<:>o! , ........ \M,. Iif',·,J fmm Smith. 11 .\\".: n ..· KMIt.., " StT1K1un· ;uKI Fun....MN' in 1I......Jth 11I..11);........· , S .....· y"rk ( ~ftJnl Unn,. "it) · p , " -\ . 11l'> 1 )
ElMINATlON
C HAPlH 11
171
plasma ( st"(, Talllt' 11--6). Only \\'11t'1I tilt" molecular \\l"1)?;ht of tilt" protemexceeds 211.lkk) tint's filtmt iun £111 ofT sharply. hnk-ed. \; 11111111>" no al bumin [molecular \\"{"i ~lIt 69,IMk) WIIlO!P) is 1I0nnally fOlllK I ill till' nltn lfiltnlh'. Ae(."{)n lillgly. as tlu- binding: o f mllst drugs in plasma is to ulluuuiu or otln-r protcms of similar or lJiglll' r mok-cnlar W{'i~tlt , us it ge,wntl mk-. unly unl xmnd d m g in pl.l~lI\a water (coneent rutkm e ll ) is filten-d (Sl"(' Tabk- 10..-1). TIlt' ran- at whid l ph~lIlit wa ter is filtered, 120 m lJmin in a in-kg 20->l'lu -oltlmitn , is t"{)nH' ntilillally calk-d thl' ~lo lIll' OI la r filtration rat e, G f H.. It fnllnws tha t 21
Role of filtralion - GFR ' Cu
Ht'l.11111hal jil is tlu- rano of lilt' unbound to total plasma drug ronceutration: therefore. Role of fi llJolion - fu' G FR ' C
22
If a t l m~ ts only filtl'R'l1 aml all filten-d tlmg is e XI're ll"'{ l Into 1111' urine. tln-n exen-rion is tilt' rail ' (If Iiltratiou. Si lll"t" n-ual d .-MiIllU', c t./{. hy de finition is
CL _ R
Role of excretion concenlJolion
til(' rollI' o f
23
pto~
it follows Ihit! for snd l it tlmg its n-ual ek-arance (hy flI tr.ttioll) is [u
' G f R. TIl l' l'xtr.ldion ratio of such a d m ~ is IO'\\'. For example, t'\,('11 if th e d rug is tOlally unbound in blood ( e ll = C,,l, IIII' l°:l..tm(>(illll ratio is still only U.II . This follows be cause
FI g . II--'l , noophlUfl ~'
Glome rulus
n..,~ I.
... 10.10. .. 1 10 11M' h""..., ..f 11M'
filt....u.." ..".I .., Tt"li..... fo"iltl>ll itMI ' 1('-
pri m.. ';!,' "~ lo II.., pnw m.al t"I.. ,J... R<-.aI""'l'tit'" 'I('"'" ..11 ,.)...'It tl.., ",-pi...",. A.i i "~.d'.nlpt ic •.,. n ul'
I" 1I... I(Ic,,,..," ,I,,,, .........it.., i.
s1rit.i .... l
, ,"- Filtration Proximal tubule
Loop of Henle
-1-- Secretion - j --
Active reabsorption
Passive reabsorption
Distal tubule
Co\\ec.ting
- tUbUle
",-brn rT1"'lC,.,t, .,,,i.dl~· ' Il'n,n in tl pr'lO..i"w1IUh...Io,.
172
Extroction rene -
EUMINATI()N
Rote 01extraction
Rote of pres.entotion
=
GFR· Cu Renal blood flow · Cb
CHAPTEl! 11
.. 120 ml/min . 0 11 1100 ml/min
.
Inulin , a n l'xogt' 1l0 1lS polys acc haride. is nett hcr hound to plasm a p r oteins no r secreted. and all the filteredload of ( ' ll(..h substance is exen-ted into the u n lit'. Al'('()rdill~ly . lh(· renal clearance is a II W a.S Iln.' of GFR. Under normal conditions. C Fn is rdilt i\"t·I~· ,..tilhlt, am i inscnsitlvc 10 cI lall ~l's in """ 11<11 hluotl How.
Adive Seallion Filt r ation alwavs occurs. hut as shown above. extraction of a tl nJ~ Iw this un-chamsm alolle is 10\\.', lospt'<.1aily if d n 'g: is highly ho und within blood. St'l'rt't io n r,;d litah 's extraction. Mt"Chanisms exis t for secn-ttng acids (all ium ) and bases (cations], ind mling: (I"a t(·mar~.. ammonium compounds . Imm tilt, plasm a info tilt· tuhnlar lumen. T he !i('('rd Ol) pmt'('sse s an- located p rcdcmtnantly in tltl' proximal tubule . AIt1ulIIj!;1J at:tin>, these tra nspo rt sys tems appt'ar to lack a hi ~h dt,,,,trt-c of spt'(ifidt)'. as t!t'Uloust ratt'tll ,y the \~idt, va rit·t)' of sullsliUlI,('S transported by tlWIII. As expect ed. however, suhs taul,('s tran sported hy tilt' sann- syste lll 1'UlIlpt't t· ....i th t'adl otlw r. St'('rPtio ll is inft'Tn 'tl wllt'll ra n- o f excretion (CI. n · C ) t'XI'('l,(!s tilt' r an- of hltrat ton (/u . C f R . G). Stated differently, secrenou is ilppan 'nt wheu CI.n > Jrl . GFR. Some rcabsorpt ion may still oc vu r, hut it m ust Ill· lt·ss th an secretion.
Protein Binding and Perfusktn Tl u- influt'lll'(Oof protein bindi ng O il secret ion d epends O il tIl(' ('ffid t'Ill')' of tilt' secretion pnx"C-'Ss ami on the contact tune at tlll' S('('n·tHI)· sites . TIIl'S<-' conclu sions are sim ilar to tlUlS(.' dra.... 'u for 11t'p 'ltic eliminat io n. Blo(xi r(·sidt·s at till' proximal Sf'('rt·t0l) ' sues for app mximatt' ly 30 $1'(' , \ \ 1lt'1l a d m g is S('Cr('h'(L hut poorly, tllis con tact time is Insuffich-nt to transport much d m g iuto the IIlIlWIl, and al'('onlillgly, tilt' drop in d m g roncent rutiou across the n 'wo ll is sma ll. T!tt·ll. the unbound concentration at tilt' sec retion silt' is alm ost ideutical to tlu- unbound concentranon in p lasma . CII, Silll't' tilt' rate o f se-cret ion depends on the unbound d m~ cnucentratiou , or C. it follows that c1t'a rdlll'(od ill' tu sec rencu, obnum-d hy d i\id in~ rate of secretion by C, is d ift'l1ly p ro portional to As va riat io n in renal blo od Aow t1IX' S uot l'iIlN ' im)' cha n/o!:t· in the plasma drug concentratlou. no (:han/o!:t· ill n-nul d t·ar.llll'(· .... -ith pt·rfusioll is t'~)( '(1('t1 under tltt·S(· circumstances . Furtln-rtuore, tilt' su m of dt·ilr.lIlI'('S il-s_~()l'i alt't l wi th filtration (/11 • G FR) and seen-tiou. must also he di rt'(11~' propo rtional to / II , Obviously, tilt' extraction ratio o f such a t1 m ~ is J(""" , Flgun- 11- 9 supports till'S(' pn-dicnons fo r fum st' m idt· in an isolah 't! nat kidm')' pn-parution . Furosemide is !t('Cn 'h'( l and is boum] to albumin. In thi s p repa ration till' fract ion unbound could be varied o\'er a w-ide r.1n~t· . SOli\(' d m j!;s are sud . excellent sub stra tes for tllt' S('('n' tol) ' sptt'm that tlwy an ' \it1ually completely removed from blood \\itllin th e tilllt' th ey art' in luntad \\ith tl\(' ilt1i\'(· tr.IIlSport sitl-·. t...·t·u w!lt'n tltt'}' an' hound to plll~ma p m teins o r l(x"db '(l in h l(KKI l1·lIs. III sudl ( ·il<;f.·S . t....i deutly disSlxiation of tllt· d m ~-p rolt-i ll (1)ll1p lt·X aml mH\l' lI1t'llt of d m~ out of til(' hl(KXI <.'('II.~ is suffid t·ntly mp id so a.~ to not limit th t' Sf,(·ft·IOl)' pnx'('ss, Pam-alllinoltipp nril' add (PA H ) is handl ed in th is lTIiUHlef and is not rPabS(Ir!)(>(1. Al'(:(J n l in~l y. til(' t'xtfllt1ion mtio o f PAil is cit)$(' to 1.0. aml lw ul"C-' its ft'n al bl(Kxl d t·ar.Ul('(· is a lIWilsn n ' of n 'n al hl(KJl.1 lIow . O h\iously. ulI(lt'r tht'S(' drcm m ta JlI'('s, dea m l1l,(' is perfusion mtt·· lim ih'll. Examplt's of d m gs ....i tlt a \"arit'I)' o f n 'n al extral'tion mlios an ' Iish>(1 in Tah lt' 11- 2.
Jrl .
Jrl,
Reabsorptioll Heah St.)'lltioll is th e thiftl fa<-1o r <-1)n t ftJll i ll~ tilt' rt'n al handling of d m~s , Ht·ahSt.lrpti oll mus t OI'(1lf if tilt' n 'n al d('amfl('(' is I('ss than tilt' l'iI!t, .lalt'tl d t,.mllll,(· h\' filtmtio n
CHAPTE R 11
flow • Urine coocenlfation P1o,mo co ocenlfolion
ilIl d
shu v e u = [u .
24
e, it folluws that
5 C
E
:::J 4 E
~
u c
• 3
FiX, 11-9,
"2
1.' 10 II.., 1,,1;11 n'n;a]
{-It'.nuK'" (al or run..... Ill iclt- III diff..... " 1 ,·",1,,,.. "r
G
~
" E
~ ~
,...... ....-_.--.... ....... .... .......
0
"
~
~
0
Con l ri h"hco" of ~", ..'n,lar Iih r..l ic..,
iel ,uKI lul",lar ...-e-n'h""
~ ~
o
0.2
0.4
Fraction Unbound
--_
_
0.6
0.8
. 1.0
frar.1ion " nhou nd. (Hall. S.: Dod oral diue rtalion. UnMmty or Manchl:':
"4
CHlV'l'E1! 11
Renol clea rance "
fu · Urine flow
2S
Thls last f"(·latinmllip is it simple test of how du,'>C.' n-ahsorptiou is 10 equilihnum, A dmg muyhave a re nal d t ' a nllll 't ' hduw this \ 1UlIt ' if iI is ;\<.1 iw ly n -absorbed. ~ l un"( J\ t·r. if dr ug is highly bound to plasma p roteins, n'lla l dt'ar.u\('(' (ami extracnou mlio ) would l)t· exIrt'IIJt'ly small since II rine How is nor mally only I to 2 III IJ min. :"on- also that n-ual ck-arauccis tlin'<.1ly p n llxlrt iuu,t! to fil. ",11('11 u n lit" lIow is constan t. Ethyl alcohol is an (·xalllpit. o f u compoundthat is 1101 siWlifk-anlly bound to plasma pmh-ius a ud is n ,,,h so rh('(!lo the extent thai its coucentruttou in uri ne is vi rt uallv till ' s., ami till' d ink-Oil state of a patu-nt. It aiM) vuri es t1 u ri n ~ the day. Respirato!)' and nu-tabollc acklosls p r oduce s add ifi<."ltinl\, und n -spitu tory an ti metabolic alkalosis produces alkalilli7"ltio ll. \\1Wll metabolic addusis is of n-uu l ()ri~ n . fo r example. renal tu bular addos is,lht, urine is alkahnc. D m~s s\l(:h ,LS the l'Olrho lli<' an h~l. lm..t' inh ibitor, aeetnzolamide, p n khll't' an ,uka lilll' urin e. Equilibriu m (,'on"id~ral jml1l, Rt'llal clearances o f s('\"('ml wt'ak add.s and bases, listl't l in T ahle 11......1. ...."t"n' calculuted usmg E(I' 24 . The urine-to- plasma ronceutranon ratlo was calculated using ti n' Henderson-H asselbalch cquatlou (Chap. S), gin'n that tILl'S(' compounds do not hind 10 plas ma proteins. thai equtllbrtum is "dlit"\'t't.l between nu -tomzed (I m~ in urine and plasma, and thai ti lt' i0l1 i 1~ 't 1 fon n is not tlifTlIsih ll'. It appe"l'S thaf rlurenal d ear.IIl<" · of SO liit' acids , p Ka less than 6.0, can 1)1' mu('h It-' s than llrill(' lIow ( I III Ij miu], whereas Ihat of all>' base cannot. because uri ne p i I is never much h i ~l lI"r than plas ma p ll . ....n i ll tt' rt"Sti ll~ ull'it'rvutio ll may 1)(' nmdl' " IJl Ull w('ak b,L'it,~ . .\t low uri ne pll , n -uul d (' am IK" , hy calculanou, approaclu-s n-ual blood Row, which usually su ~('sh "ti in' sa-en non. It is unlikely. !JtlW("\"{'r, that such a hi ~h d f'll.r.mt'(· \~tl ll(' can 1)(' o!ltniut'(l bY !>iLssi\"(' d ifTusion- for thn'(' n 'aMlIIS. First. til(' fr,i('!ioll of l'('nal l)lood flow that n ';ld 1("s tilt' t' ml of till' d istal tuhu ll' and l,(lllt-'(1i ll~ tuhult" .....llt'r l' till' lIlajo r d l a ll ~t ' ill p I! ( )( 't.1 1I'S, is SllliJ I. St.'l.'OIIt I, the l-.lk·u!atiolJ o f n 'na! d t·anml,. ill Table 11 --3 is l>iL'it't.1 011 Il.t' mHo n f Urillt' l'lII<.'t'ntmtiOlI to plasma t,m('('ntm tion Il'a.,ing, mtllt"r th an (' lI te ri n~. tilt' kid lll')"S. ,1w n "-
,.It.. C.1c.1 W_. 11-3. Ac14l•••41 W_
_1 CI •• (_L / •••• " hlecte41 N_.....r V.rt••• V.I_. . . urt_ pH
U.41.r .~lIIltr1u. C..41It1 ... COX;
A
B C
0
,E G
~"-"
"'"
""2 '
..
0001 0 1 10 10
6' 10.4 24 64
QO
10 4
1000
12 4
1000
..
"'" '" 01 02 10 1.0 2 10 10
"3
3 10 10 09 03 03
'" conceutrut to n hen- is I. ·ss thau Ihal ('ll h'rill ~ tilt' kitlllt·ys. particularly wh e n the ex tr action rat io o f till' dmg is hi~h -a I'w rfllsiull rdte· limilt"tl u llld ilion . Tln nl . the high \'llhw s of cak-ula n -d dc'amlln ' ap ply 10 Ih( ~· ha.\I.'s . whit-II al hl ul K! Jill values n-nd tn Iw almost co mpletely iOll i7A:"(1; thus the rail' of IIll J\ "t'II1 l'1I 1 th",lI ~h rlu- JI1('mhr-.U1c,,;, "~Ii<:h dep"'lIlls Oil the coucentranou of un-lonbad drug. is n -due -d. :\ simila r af).,'ll lllt"1l1 appli~ to \\"('ak ad&•. At"(:n rtlin v;')', a n-nal dt'i mlllel ' n thll" j:!;rt'alt' r tha n jr, . G FH for ('itlw ( 0 11 ad d IIr a 1I0 11S
ha.\!:· al non nal u nne I'll pmhahly SlIMt'Sb alii\'{' ~'(.' r('li ll" . A Ra' r P NJ('('1I11 ill Rl!ality. Til t, f( ln ~oi ll V: d iS{'ll ssio ll W,LS IliL'it"t! primaril)" 011 ('(Iuilibrium concepts. hut Il
...
ceo
~
A
"'~
B
2.4 64 10 4 24
C Bo~
0
E
..
,.. 10 4
G
12 4
" o.ocos
0 .01
1.0
3
50 100 100
W
100 W
10
6.4
F
........
W 7
100
50 0 .0 1 00001
0 ,0001 10 - 0
97
0.3 0 .003
~
~u x
w ~ c
t"l1l;. I I -t O.
Acidic Urine (pH 4.9-5.3)
6
E
i!
~ ~ O
nIt1 h~i.a"' p...1 ","i ll"· in
12fi 1.
4
EE
2-
"
::;; 15 C
2
No pH Control lkallne Urine 'l! 7 608 2~
~
0
E
-c
0 0
4
Thon lll lu1.otr.l' ll riRl" J_"rr h"" "r
""1,,.11" 1'1"1;1.1"1'''' (11 mil ur.lJ,·) In " U.n ",.riM " , 11, tl... uri,1<' I'll . (Ao Lopt....1 frn," I\<'(·krt l . .\11 . ;,U .. I It."",-L.,ttl. \1 ,: ViiOWl)' ("U"trh<", l.i'M·lic:" flf
8
Hours
12
16
1 \lfi.~J
frulIl ,
1';<1"..... ZtM'i :I2fit lo--
176
OW'TE f 11
1111" un ne. wh il,' addifil';.llinll II\' i ll:l:l'Sti ll~ anunoniu m (·hln rid,· n -sults in 70 10 Mt% rt"'l' t",'ry in till' urim- Clt·arly. for th is ;Im~. unue pit is importan t ill dl·lt·n ll in i ll lo: th,· l'(llIl rihlltin~ of 1111 ' WII"I " Hilt' In tot al t'liminafju!I. Unde-r ('o m litium (,f nn pi I contr ol. II n nt · p l l varies t1lrnll~t.ulI l lilt' ,Lly. atu] tI... ewn-non o f md halll phdamilH.· lIu(1 \1d l l "!lo '1('t'l JR li ll ~I)·. nit, t·'pl.uMfioll fur t1w<,(' oh'ot'r.-aliolls is coutaim-d ill Tabk-s 11- 2 and 11-3. .\t In", UriUI ' pll . both {'Ill ilihrilllll .1IIt! killd iC' ('tlllsidt ' m !in lls (anl T hi ~t. n-ual dl'"rdI K'I ' of ;J. h
,I.,.
I. .\ h.,'\it· (ImJt th..1 il' pu!' lr ill ih III1-iu lli7A't1 fonn jl' nol n -ah..urh..'tl. n pnlk '!'l' of Its ..It")!:n..· of iun i:f..aliull in lilt' urtm-. 11111..,,\, at.1 i ' I · ~· Iroln'\purtl't l. The ;lInil~~'{,,,,KIt. ~·Il la . midn i.. lin 1",.lm p lt·; its n -nal (·k·a r;uK't" is ilHk·pt·nd(·nl n f Unll(' p l f. 2. A \t'ry Wt·OIl1)· IJa.,\k· nonpolar dnl~. whn~.· I'M b an MUlti 6 .11 or Ill·lIM'. '\11t·1I ...'\ p m Ill)\:)l)" t·lll'. i.. t'111'II'\iH'I)' n ·a1N:ln lt-d al al l va hn -s of uri ne- p i I 1 1t '(~.tU ....•1I.... I..nent of (I nl~ in tI.... tlifTu'\ih l..• ull-jo lli:fA't1 form i.. l'u fTirit'nt 10 han' no Iimitin!! 1·1T1'(1 11I1 its ran- u f n-al.. ,orpt iu n, n1!an ll,~" uf urim- p ll Furthe-rmore, t'l illilih rill lll fa\'(n~ n';lh~ lrption , Tl w n ·n;d d t';mIlK't' of l'1l(:h a dnl~ lIlay vary with UO nt· pH hut its ' 1dm ' il' Illw. t'!'lll,(; ;'Uy if 11...• drug i.. h i ~hl)' bound tn pla"lIla pRll t·ins . 3 . Fu r a , Inm!! b..L....• ~illa a I)M vahn- appRiadlillK 12 ur Kn· ah· r. such a... !!u ;lIK·dlilliIW. litt l,· n r 110 n·aIKl,rp tiu n i.. (·'I)('(1I..:lth m llgho1l1 til(' mll~I ' (If unlit' p H hl":'allliC' ionizanou i.. \II ,·,h'nsiH· Ihat it lilllil'\ tilt' ran- u f Il"alxorpt iu n . A('('t)nlill~Y. n 'II01I d('arollK.'t· is im k·· IIt'nd,,"t nf urtue p ll 01 11(1 gt·ll('r.l lly hi ~lt . -' Fllr ;1 ha...k lIollpoLlr tlnl!! ";1" ;ll,Ka Ullm· IN·flu ·.". 6.0 ",141 12. ti lt' t'lh'lIf of n ·ah.. \I,rp tillli ..-aric·s fmlll IIt,!!li¢ hlt· 10 allllmi ('t)lIIpll'f!' ..la supportin!! till' t·'I)(..:1('(lurill(· p ll !o(·II..ithil)· ill n 'ual dt·amlln.· u f nonpol;lr wt'a k add.. ~i l " '1 p Ka IIt·t\\..'t·1I 3 and 7.5 :IlId nonpolar ~,·al. h .L.....l' \\i tl l a 11M 1 1l '1~ 1 't ' f1 6 :tlld 12 ;tn ' pnl\idt 't l l~' Solli(.,. li(· add . ,JM 3 ( FiJ:. I I-II ). and tl l(' auIIK·llllinlit' ..lil·t1I) k';ln );l. 1II'l:fillt'. IlM 10 (T
'IN'
CHAPTH II
171
El.WoI'lATI()N
250
1,'1.. . I I _ II . Tt,.. unb.....,,1 rl· .. ,,1 d ";If"'ll" ,/ w1ie::o-lk: ••d d i' llTU ..... .1r""'"t k ...lI ,, " 'ill. ..." i1.l'n ·u,' , ,, uri".· I'll " I.M· 6.S (A,LtI'h'<1 fn.tI, Smitl, I'.K.. (;1.. ",u1l. II I. .. Sta ll . e.G.. ",..I (~"" .;Il.·k. S., Sh..lio.....tI tl,,· Iw'.tm ...... h (l , of ....lk, -lott"S J 11""0 ".'04 t:~p. Ttlt·r.. .'J 7:21; - 2.').';. 1946.1
• 200
• •
I
•• •
o 5.5
6.5
6
••
•
7. 7.5 Urine pH
8
8.5
'.~I. 1 1 - 5 . h ".ltI.lty" DI.ttt,t.,.rIHI. . ... . a. _I a,,_IN• .. Ch..., . I.. Uri... pH·
Not coonolled r-6 3f Ac..:!,c, <55 Alkolme, > 7.5 ~"""
t"",,", G h i
"""'''' ,noou '" cloo.oi'o,,,,,,,t:o ""' "I\i>
86 38 0
10
A '" ~ v ~ ~" Onnt, M l E , Cd I] 1101--8 12 , 198 1
12
t·I!t. 11_12. R.·•...! ,....;1.. . . . . ., • • / Iw,,·•• w>art 'ilal , ,.,.. io... " i tl. Urill<' iteM' in I'WlI. It i. oJ.., ;0 f" "d ielf' uf Uril1l' lIl t " , Ih""t albiitlil..diull (hi....."
~ .2 0
c
~
~ Q.c
15
E
g
E
8 •
~::>
~ -
~
..'"
• •
4
•
'-'
•• •
c
~
"'
0
•
•• •
•
• 0
4 8 12 Uri ne Flow (mUminl
16
CHAPTEI1 11
"I
shows how tln- renal clearance of plll' lloharhilal (" Kit • .2 ) va ru-s wit h u rim- Ilow . As ex{X't.1('(1. tilt' re nal clearance of this d m~ is p l l M'lIsit in ' ;L~ well as urine How-rate <1('1)('11<1.'111. Fo~"(1 Diuresis a nd Urine pH ('..u llin)!. I II(: r( ';L~"( 1 u rim- tlow by fnrt"l:'tl intal .· of 1I I1i{L~ and . in sorm - cases. rln- coad m lntstrutiouof mannitol or another diuretic. m il Incn-aw the excretion of some dru gs. More rapid cltnunanou is, of ( llll N', d.'simhl.' for tilt' P U '1)(IM' of dd(}xif~i ll g a pal ient who is overdosed. Several criteria must ' ''-' TIle! for fOR.'t't1 d iur esis to be of value: 1. Ht'lml excretion under condmons o f (nn:'t'(1
2. 111t' compound must normally bt· t·xknsin ·ly n-ubsorlx-d ill till' n-nal tulurk-. 3. If till' n 'ahso rpt ioll ts p I! sl' nsili\"t'. both fom-d diu n-sts and p ll control ilia)' he of vulue. 111is applies if forced dilln'sis or pl t control alonl' o nly pa rtia lly pn-wnts n-ahsorplion , TIlt' last point bears further discussion. SUPIX)S(' thut, o n alkalini7j llg tilt, uri ne, till' n-absorpuou (If II weak add is decn-ased from un to )( )<;f of Illal Iilte-n- dand seen-ted. 111l' lltklilioll of fon ,('ll dum-sis \\ill he of lild ,' addi tional \"01111I' ; Ill(' ewn-tiou r an- can unlv lit, tucre ascd by a furthe r 10%. 111e converse app lies In tln- \IS( ' u f p I! ('(JIIlml wlu-n fUR't'11 diun-sls almost l'tllllplt'h, ly PTt"\'t-'1I1s n-ubsorption.
Renal HandGng af Pratein Dng. As SIl()\\11 in Tahlt, 11-6. l!l'lTI~', espt"(-jall~' l c ,,"\' lIlol,"('ular \\'('ighl. p rott'ills an ' subslantially filtered in the gim llt·m llls. yet !itt lt, of till'S(' an' Ilsllall~' found in urine. 11lis low ren al c k-ara uce o f proteins ari ses Irorn t heir metabolism in rln- proxuual tubule. I" ,,",' I!lO!l,,(11Iur wt'ight prctetus an ' Il1t·laholiJ'..l'11 by t'1I1.}1111'S 10(';.111'1) ill tht' lmrsh bo rder (If tln- lumen, WIll'n'ILS high mol ecular weight pm lein.s of tln- Si"A' of alhum in an ' transporte-d tnt o tilt' pmximal tubular ed ls I ~' t' lIdo,-')tusis and uu-tabohzcd then- b}'lyso wmal t' IlI.}'llll'S. Gt'lJ' emily, ('alaho lism of p mlt-ills continues until tilt' const uueut am ino ad d s are formed. The amino ad ds an ' then (.'t I!lS( ' T\1'1 1 h)' rea bso rp tion into till' \ 1L..culatun-. Althou gt. ljllaTllilati\'1' data art' spa rst', it aplx'ars that for sonu- proteins. and prtlhah l~' also p rotein dmj.,~ , tilt' kid ney is a, if 1I0t tke, majo r O~lI ll of elmunanou ( St.'!..' Disease, C hap. Ill; T urnover COIl("('pts, C hap, 23 ).
DEPENDENCE DF ElIMINATlDN KINETICS DN ClEARANCE AHD DISTRIBUTlDN 111(' physiol~' o f tilt' Ixltly d il'lal('s Illat several plmrma<.'lIkilld it: panllnd t'rs .ITt' n-latr-d to am i dt'llt'ml,'n l Oil 0111' another. Pt'n mps the most Iuudann-ntal dt1lt'lIdt'lIl')' ill cltnk-al
lATWUVn CON:::f Nl V TJ:)N fVo9M. CONC INTUTlQN
InloUlin Myoglobulin Grov.m hormone
0.000
0 8Q
16,QOO
0 75 0 72
Superox~ di~lJlo~
20.000 32.000
0 33b
Beocepo"
44 ,000
008
A1bvmin
eo.ooo
OOOl e
E1r.MlNATION
CHAPTn I I
phamlat'tlkillt'li<:s is that of half-lift, d('P"'Ill]('IK'Y is d('ri n"tl ;L~ fo llows .
0 11
"9
(t nta]) d t'amll(.'t' ami
'1111l 1l1t'
n f dlstnbunon . 111is
Haff-lift in pJasmo Hecall from Ch ap . 3 th.u IIU' ehmination mit' constant (i.e.. fr;H;tional rate of drug (·Iimina tion ), k , is n-lnn-d to total ch-arauce. Cl., ami vulunu- of dis tribution, \ ', hy the exp res ston k ..
Rale of elimination Cl Amount in body ..
V
26
Bt'(.·;tIIst' clearance is Iht' volunu- of pl.LslIlil ck-un-d of dm~ pt'r unit n f lilllt' ami \' is tluvnl u uu- that drug apP"'ars to {1("i;llpy at a t'tlllt't·nlralioll ("{pia l to Ih;11 in plasma, it is ap pare nt Fnun El l. 26 thai fmt1icmul mit' o f t1m~ r-lnninunou can Ill.' thll ll~hl of ;LS tilt' fm(;lion of tilt' volume of d islrihillilln From whit'h d n l~ is Tt' lIlll\"t"t1 pl 'T unil tiuu -. Furthermore, n-cnll that lIalf-lift·, t l !\!. is n-lated 10 tc . or til \ ' and el. Ihmtl ~h th t' ( 'X pl"\'Ssio lls
-
0.693 0.693 V --; - CL
27
Tn appreciate tlu- d t'!)('ndt'Ilt'(, of half-lift' on d t'ar.ult't' and \' IIII IIl(' of distrthution. t't lllsid('r a dmlot thai u lJ(le r'J.t{ II.~ complete t'nlt 'mllt'patk t~l.·l i Tl~ ~l' l di strilllllt'S to hil t' and subsefllWlllly to tilt' intes tines in s i ~1\ illt"llll t ;J11\Ul1l1IS a..s a n-sult of slllw intest inal reubsorptjou. 111t, t"lJlist'flllt'lIt"l' (If hililU) ohst m t1iol\ wn ultl Ill.' It dt "l.'n 'lLS('(1 voluun- of distrtlurtio n, hul no t:h all ~t' in lotal elea raru-e, and therefore a sho rter lndf-bfc. On th e othe r hand . if there is no t'll!t'ro llt'p:t1ic (} \'Iinlot, tilt' hil(' am i tilt' intl'slim's an' not P:lrt of the \'o tUIIU' of di stri h U!ioll, BiliitTy nhslOlt1ioll . hy dt 'i 'n 'll-sillg d l'amnt't ' \\i lhoutltlTt'di ng distributio n. \\1I 111t1 the n cause the half-life 10 iIWTeaS('. Fil-.1J.Jn.' 11- 13 illu strates hal f-Ii\"t"s (If dOl~s wi th cu rious ('(l1nhi na tions o f d t'ar.llIi.'t' and vnlu lilt' flf d ist ribution . \ \ 'ln-n d l'am llt'(' is 11Iw ami \"(111I1I1t' o f d ist nbunon is Iltr'J.t{" tlu- !lalflife can Ill.' wee-ks o r montha.Tlu-n- is a paudty o f dOl ~ c-conples \\ilh these characte-ristics . 11 lis is not s ll rpri s i n ~, as d nL~ acc umnlut ion wnukl Ill.· t·xh'1\sh'(, and occu r s1nwly 0 1\ t1;\ily dusi n ~ , Furtln-nno n -. rk-toxifi canon o f a patient who exlublts toxidty while nil such a t101 ~ wu nlt! Ill' slow without intervention.
HaN-life In Blood and Plasma Wert" 111(' interrelationship s t'\ p Tt's 'it'i1in Eqs. 26 and 2. an' just llS n 'ad ily derived from d t'a mll("(' and " ,lu fTlt' par.1II1t't t'TS II
of eliminction .. Cl ' C .. Cl b • Cb ,. Clu · Cu
28
am i Amount in body ... V " C
.. Vb " Cb .. Vu · Cu ~ ()tt ,
29
th at each dl'ar.mt't ' o r volunu- te-rm can 1M' n-lated to tilt' othe r using: the dehni tinllS
...
CHAf'TE ~
flMNATION
11
I II "" Gil l e illldji'j, = e ll IC!>' For cxnmpl••, C l. "" [u . C I.A1. n i \i tlill ~ each tcrru ill Eel_21'1 hy tilt' n ·sllI.·t:fin ' term ill E,,_2H ~i\"('s
k _
CLu "" Vu
30
uud Oil s ll hs l i l ll l i ll~ Eel _30 iu tu E 'I _ 2 7. it follows t h aI
'0
'9
•
20
• 22 ••
100
2'
23
•
30
•
' 000
10,000 (hours)
1000
'0,000
Volume of Distribution (L)
nit. 11_ 13. ( :I.... r..'Il~· (" n lm,d.·) "",I ...IIIIII<· .. r . I"l nhu ticm (..1....;,....1n r ..•.. "'-1...1t1rup ,.. ~- ...iolo ·I~·. n" · \b"~ " ll4r , ..1.. 0. .. 1 1"..-.; . 1.."" 11M' n m ,l,h...lic" " o f .-!t·ar;<'J<'O' ;o'HI \~~ " nw will, tI,,· "... Io"lf.llf,- (IM,u n). ~ "I<" 110..1 .I m~ ..i tl, "'" d .·;tr.Ull"l'" ..".1 1,,'1'" " .."', (ril:l,1 Ie"",", '1"...lnllll " f I{r"r>l, ) ;u ".Iiffi<; ,lt I" lin.l: tl..-tr hal f·hw~ Ito.'
It.,
" tl<'l1 10"'1: fur .10,.....· ,lml«l<> I,,· " 1 r r"'1i<-..tI~· ill .Inll(1I"'r"l':" (A,!..j>l,..1fru ", Tun "., T :'\ .: C'''K''l-pl.I....'k t" 1,1,.. r",.•,,,,l..l n<'lI<". 11,..rtIl.Ol' .I. n lt·•.. 12. 1l1!j...1 31. I~ I U....I "..ill, p,-m'l... f .."II.... ;1.".1 l"'hli.I,... .) n ...In' l:' "no ..' f"II.......: I)ij.("" in I 1',·" l.; 1I1" v l:l. T..t r...:w li' ''· (;"'IIa1J,,,,,,, 13. ( ;' ·III.m ,id " z '\' p lo " 25. l) iov' l );lI" a I ',·" id ll", r: 1-1 :\ ",lLot; " ~ ( » ."; II,,, :26. (:..rt"''''''''A,.'''15. n " ' '1,I,}1Ii 'w If> ."..ivt,h ",i d. 27. S" lfa"..-rv i,...) t"llm.. 17 s lllfi.. nvJol.· 2\ . \ ·..IP" Jit.- ." dtl h . \1 ....)'111"'-; \ 1' l ,,-o ,li"•• ... T" II..'I.."' l...· W" rfari ll .111. ." ", ic.. Lt" n.... l'r" I'....u"ol.,1 III 1>O'....," 1 h~·Il"' l rnm' l".· \I I'ro ll·,un_., ni," .11 .""'rI..",·,;";,, II :lll 1>o. " ' 1'l" .12. 1'1..-,..oI...rtril..l III C)" ln idll'" 2 1 cJ ,l<.rp"''''al ln':).1. I) ll:illl. in I I ( :Io I" ra" 'I'I"·lIit.d 22 :'\ "rtri l~ li". ·
i<." ..
,".
·",lt"·
'"
ElIMINATlON
CHAPTER 11
' 1/2 =
111
0 .693 Vb _ 0.693 Vu CLb CLu
0 .693 V CL
31
T hus. lilt' value of Ihe eliminatinll rail' constant. k, or III(" half-lift", t lr
STUDY PRDBlIMS (Answ ers to Study Problems a re in Appendix II.) I. Th e renal ck-arances and till" Iracnons unbou nd in plasma of th n-e dm~s in u 'O-kg sllhjl'(1 un- ;LS follo ws : Renql Cec-cece Iml!m,n)
Theophyll,ne F'henyloin
Cetoerod
10
0 15 20
f' OCli()n
Unboul\Cl
0.50 010 0.02
State the likd y lnvolvemcnt of filtra tion, secretion . an d n-aleorptton ill Ihe renu l hall(",It·1i o f the-se- d m /-.'S, wheu GFR is 120 m[) mill uud urine flow is 1.5 IJI I/min. 2. Fo r r-ach of till" follt MiTl~ mult iple d lOil't" qu estion s imlicate Iht." let ters o f all (om- or mo n ") of tilt" co rrect answe-rs. Hrid ly comment 0 11 why th e others an" nol ('\)fTI"(.1 . a. 111l" condutons that ind it'llie till" probability of rena l d t"amlll"l" o f a w,"ald~' acid ic t1m~ ht"ill~ S("nsilin " 10 uri ne p H art:' I. " is Sl'(.Tt"l t ,\ 1 am i not reabsorbed. 2. It has a pKa vahu- o f s.u 3 . II has .1 small voluuu- of d islribution. 4. All of the d m ~ is n'nally excreted unchangcd. jc = 1,0 , h . FOf(,\"(1diu resis is likd y 10 en ha nce signifil"llnlly Ihe el iminalion kiuencs of a tim.!: I , \\11it-h is bolh po lar and slowly removed fmm tilt" body. 2. For whic h mos t of Ihe filtered and S("(.'n "It"t1 dm~ is n-absorlx-d aud is ~n".t1l"r than 0 .5 . 3. \\1lidl is ne-utral , pola r, am i hilS a \1.lllIl" of/ ,. !!:n "aIN thuu 1),9. 4. \\11it-h is not secren-d an ti for whit-h till" rano of its unbo und n-ual clearanceto ('n "alillim" cll"afimn" is l.O. e. A n -uul h lnnd d t "afiUll,(' of 56i mUmin for oxaci llin Indicates tha t : I, It is scen-ted inlo till' lum inal content s of tilt" neph ron . 2. Its n-uulevtract ion ratki is 0.1. 3. TI lt" majori ly o f ti m!!: t"nlt"rill!!: Ihe budy is excn-h-d ill till" urine ulldl.
ie
CHAPTH 11
112
Fract ion of fi ltt,r't't! and ~ '(:n' lt '( l
3.
A l'( lIIS I 11ll t
l 'a~l l l" l'I
tln-ir findings . a.
K Il(,"in ~
tim! ;lkollol is not bound to l'(lInpo llt'nt s in hlood. whai esplanalillll(s ) ( ';11I " t ' l\\ l '( ' 1I cono-mrattous of ail-ollol ill hlood and ill uri ue? h. Would you (''''1')('<.1: the excretion rate of "!m hol to corn-late \\; 111 ti lt' blood alcohol } U II
olTer for tilt" \'l'ry dost" correlation
('tllll1:°n l m t io n? D iM.'US-\
lmelly.
T..... , '.7. 'NCI.-cy D..trllMrtI_ .. the .......
AIe.h.r C.IIC.lltywt1.II••
UrI_'''ee4 Percent d ~1I()n$ \Jnne ConcenJl'ollOn Blood Concenlfohon
51
9
8
J2
1 2-1 4
>16
1.4-16
4. T lln"t· d mWi art' hsn-d ill T abtt· 11-8 t<~et her wit ll sonu- uf thei r ph)~ i ed l pmpl·rties and disposition characte-rist lcs in 11 'j'n-k~ limn.
,..... "
...
~ny~Q1.AU,(;Tttf>T1C
Polo"'Y d unionized fOfm pKa
_... Polo,
30 (wea k codl
250 25 0 .1
U$lIOl ~ [mgl
VoIvme 01 d, ~" bullOll III F,oc;toon "",bovnd [M Holf.lile Ih'l Froctoon exceed unchanged llei
a. lndican- till'
I
027
d m~( s )
-, '''''''''''
00"""'"
""'''''''', on ccd
90
Not
[om,ne]
0< (]
4D0-600 210 09 14
bene
350 245 006 8 <001
Ol d
for wlJk h ('adl of t1w follnwill!!: stil!t' lIIl'nts is pmhahly must
appltcable: I . 11ll' n 'II;11d t·urdlln.· of tltis d m !!: is th e most wusith"(' to d l,Ul!!:('S in urine- p i !.
2. 11lis drug hiLS till' hi~ll('st n-nal d t'arallt't:' of tln- thn-e hstcd. 3. This tim" most likd y shows the " n ·;tll·st d ilTusio n lunnauon in (: mss i ll~ the piacenta 10 the fet us. 4. Foro-d dam-sis is most Iikl'1y to 1)(' o f
value for this
( I m~
ill a l'L...· o f dn l~
overdose. 5. Fo r 100 Ill ~ ill the- I)(llly. tla- p l.L\ rna coneeutrution is hi~hesl for th is drug aftN d istrihutioll e-quilibrium is al:lliewtl. 6 . Thi s dm~ ha.s til(' lo\\\'st total d(·ardlll"t·, h , C irdl' tlu- must appm p riillt> word. t N IU , or \ 11111(' (of those sho w n in italit~ ) for rlnfollo.... ill~ statements: I. 111t' n "II;11 d l':lrdlln.· o f nafcillin will j rlCn'(IS('" d~'Cn'(I."f·•.shOlt ' l i tt ll' elm'l /!." if tlud m~ is si~lIifit'IU I I,· d isplau:t1 Irom ptL~ Ill;l pmh 'in bi ll tli ll~ silt'S.
113
CHAPTER 11
2. For tilt" d m~ with a n-nal cleanuax- that is lIlusl st>nsitin> 10 changt'S in uri ne p i I. tJlJ." l il.i:.tltiOlI , fI('iflijimtim. of tilt" urine .should dl''C.' n·il<;t' th e ren al ck-arauce . 3. ~ af('jlli ll ~~, h .wt rhst rtbun-d t...·(·nly throughout and '1<.'(.' )IInt(-<1 fur wi thin th(· cxtmcellular flurds. -I. Cyduspo rim' is p rilllilrily t'lilllin "h'i.! by "..1f1iJ"li.ml , n "lm/ loxO'I'ti' l/I . 5 . Cydospo rillt· ran. rannot 1)(· highly bound ifu les s limn 0. 1) 10 plasma p rotems Sillt.'(· it has such a largt· apP;'l n 'lll velunw o f distribution. 6 . .51,97, 99, 99,9 '.f of tOl"aillidt-' in the hody b )(J("lIIf'C! oUh ide the plasma. c. Ind i('alt' 1111>d m~( s ) for whlch eac h of the folltJ\\i n~ stat ements is 1II0st applicable. l. After all i.v. bolus dost" 30<], remains in the I)(Kly OIl 24 lirs. 2. (;i\'t'll t...·t-'I')· S hr . tht s d rug \~i ll Shl J\~' the grea test t!t'g rt'(· of accumulation. 3. Tl lis t1n11-t \\i ll ac hil'n' ti ll' 11J\~'{~t plasma eoncentrutton at plateeu foll' J\\i n~ a ('tlllstanl-r.llt· Lv. infusion of 10 mW'I T . ... \\'he-n Ill(' usllal dcN' is ad ministt-' rt- l a rgl~t ACe . 5 . Fol1 f)\~;n g :t l'flllsiant rate infu sion of 20 mW'lT. this dmg is (·xpt"C·It"C1 to ac hil"'"(' tilt' hig:hl'St pl:lslIl ll1ic hillil\' lila· hilil)' flf tlw dmg d mpt'ri dol From a rectal d m g ddi\"t'f)' <1(...'ice \\~L~ a.50. Gi\ "('n th ai thl' hIc MM.l-tn-ploLsllI;.I conccntrutiou r.ltin of thts eln lK is l.0. and Jll~Ii¢h le' unchan ged t1 m g is fou nd in urillt' follu\\i ng i.v. ud ministranuu, to what exte nt ('emld ht'lJil tk' HrstP ,l" \ dim in;.llion ,t('C'(111ll 1 for the loss of billil\a illihilil)' ? 6. In Tal lie' I I -~) en- hstcd some pertinent pharm acoki nenc data. fol)()\\ing administration (J rall~' (t;'lhld) alltl illlran'll(lIIsly of a HKI. mg tkN' o f a dm ~ to a 6S-k~ sllbjt"l1. TIlt' bloo d-to-pl.e um concentr ation ratio of th e d mg: is O.Ti ,
,.It•• 11-9. Intravenous
I,Q3
0"
0 22
105
1 22
a. C;.II(: lIla((' tht>ora l hi' lil\Olilabili ty u f the d m~. h . By appropriate calculatlou. ('Slima tt· 10 what extent tltl' Ilbst·"' 'e 'i.1 hi' lit\"ailahi lit)· llli~h t 11(" a!lrihu!t'i.! to finl -p'l"S h"IJillk dimiualion .
I NTEGRATIO N WI TH KIN ETICS
OBIICTlVIS The leodef will be able 10: 1. li!ol example 01 physiologiC vc.cbes tho! may o!lel me p'In"lOry phormocohneHc pcrceelen: o~pnon role constonl, biocMJilability, bepcnc clearance. reno! clearance. and v0lume 01 disrribull()l1. 2. Given pk»mo 101' bkxxll concentration verW$ lime dalo in normal and cseed sscies. determine the changes rho! hove cccoted in the primary and seccodcrv pholtflocol"neliC poromel9l'S and list the pouible physiologiC mechanism/51 i~ 3 Predct and gfophicolfy demonwole the effecl$ of on checnco in poseo prolein Of nssoe binding. perlu$ion. Of metabolic activity on the lime course of drug in blood when !he oppl'optiore plirnary pharmocokinetlc pafOITlE!fefS ole k/'lO'Wll. ~ Predid the phormocologiC ccoseqoeeces 01 each 01 the alterations 9'\'$1 in ob!ecJive 3,
HI'fPrt 'Iwt · h frt 'II'lt'1l11~ lIh1d.· loll... \ allll' o f 1I
tlu·rapy. .uulr-o-n \\; 11.111 tilt' \anll' illdi\;tllIal ";11. lilll" , :\ 11 "llilil ~ 10 " "j ~1I lil, 'I~ ph ysiol "!-.'ie ;lll{IIMtb ol,,~ie lII' ·,:I.a uis rm 10 tlU'S(' oh.... ·n ,,, I eh an~, ·s in tln- lilll 'lie ' o f a elm !! i' importalil . " , i' IIn- prr-diction of IIII' kim-tu-'~ lI l""l jl "' lll"( 'S o f II(~ ' ph a n- l-,'i\( ' Il. F rl'ljlll' lllly. ('o lll iitinn' 1",,1 prtltlll("t:' a d la ll~( ' ill Oil" phy,io[, ~i l ' ll;lrOllllt'h' r (';\11 ...· (·!I;llIg,·, ill ll llwrs a" we·11. Fo r " "Impll·. n 'II;11 (' ..it uat ion-, i' a g,lt ltl ' ·\;l1 n pl,. Ill' tlu- lilu'l ie (, nl\" ' llU 'l' I ~ " clf any OI W o f Ill(' alll'r'll i'H1' l llill 1)('('lIr, Yd . t l«·SI · l; m!' o f oh' I'n 'al;IIIl' IN,'('lIr [n ·fl" I'lIl ly. '1'111' firvt , I.· p ill ,Ul al~-/j ll !! tln-ru i, 10 c'\ a mi ll" lilt' " \Jlt' d a lioll' for all a llt 'ratioll ill ",wit ph ysi 1,1."",'i(' \ a riah l,' ill\'I,h I" !. T ill' 11\ " rall pktun- i' 1111 '11 l!ai l lt ', I II~' inlt·c,r'lli lll.( 1111 ''' ' \·\ \It" ·I"t i.m....
INTlRRIlAIIONSHIPS AMONG PHARMACOKINITIC PARAMITIRS AND PHYSIOLOGIC VARIABLIS . \ " lII ll1la ~ 111' 1111' illlt'rn·blillmh il" ,11 110111.( p llar Hl;l11,l iltdi(' \liIr01l11l'1'·rs and plt~ ...i" rtll.(i t' \aria h l," i, appmpriah' [n-n-. ' 84
CI1AP1'H 12
,,,
lNT£GAATlON WITH KNTlC5
Primary Pereeeten and Physialogic Variables T he p rnt't'Sst'S flf ahsflrp tion am i di sposition depend Oil mml )' physioln¢c va riables. C astroinn-stinal ahso1lllion Illay lx- aITN1ed. by blood Row at the absorption silf.' , ~a.sl ric f" IllP!)ill ~. an d ~'ls t nlill tes li ll'll motil ity. D islrihution is infillt'nt't'(! by hindin~ 10 bolh plasma proteins and ti SSIl t' {'o lllpeJlleuIS am i by IxwJ~' composition. He nal excn-tion lIlay depend on secretion {active tr ansport ), umu- p ll . and unne flow. Eadl of these physiol~c vunables is aITt'(1t'(! hy num erous factors. Thus. mhh ill,l1; Increases subcutaneous and muscle blood [low, futxl slows ~a.sl ril' t' lIlpl}i llg, ami diseases and d rugs produce lllany t,ITtds. TIlt' pharmacokinetics uf a d m~ tlfh'lI can Ix-' dt's<.'rilx'tl by n· lali"t'ly Iew par.ullett'r'S . Ht"t'all that ahSflllltion ca n lx- charact erized by bioan lilahi lity am ! by an absorption rancons tant . wln-n ubsorption is first o rder. di stribution can be characterized hy tilt' volume of divtributiou; and eltmtuntlou can I>t., cbaracte naed bj hepanc and renal clearances. As d is<" usS('(1 ill Chaps. S I hrotl~h I I, each of these !lilr.lIIlt'tt'f'S lila)' be
Set.·ndt'Il<:il's an' summarized brit'Ay in T ahle 12- 2. TIll' equations in Tahlt' 12-2 plus a Iew previous equations p"l\idt· tilt>ha."jc· n-lanouships for illl l'rprt'tin~ am i prt'(lic1i n~ alterations in kineti c be-havior. Part k11larly useful an' till' lIll'lllory ulds of Eqs. 13 and 17 in Ch ap . II. namely
ami
2
Tall'. 12-1. De~IHI...c. " PrI.a.., Pha....c.kllMllc Pa,.. . . ." ... Ph.,.I.I.,lc Vanaill••
A~ptton fOIe con~lOflt
BIocxl flow ot CJl:»otpliOn~. 9'U"1C empfylng tcd}. ~nol
BI(XNClllabil,ty
~IC emptying. 1oeO"etion
motility [Otal) clearance. b!och'ailabiloty"
Hepo IK ~ena l
eec-eece
01 oeid ifl !oIOfTIOCh ced hydro/yhc
enzymes in bile. inIso$hnol motill'Y He,xl!ic blood Row, bindlll9 III blood.
Ifllnruoc
hepoIoceIIub
(lCtivity
Reno! blood Row. bonding in blood. OdrYe!lllCl'etion 00'''' ~ption, 1,11'" pH. uOf'lIIllow. gIomeruIor liltlation,ote Bind'll9 ifll*xxj, binding in 1i!oSUM, JX)'fltiorung IfllO lot. ~ compo6lbOn,
body ~ze
INTEGAATON WITH ItNETlCS
'16
D.'
r.we
12-2. Vet- _ Pri..-y
Secondo", P!>::J.'"'CJCOl,
c
ry ..... • 1
Pwr........
D.rl ...
o 6Q3 • Vo!o.me cJ cb-ib.Aon
EI,....tl(l!1()n hoJ.l~
Cleao>a
EI'''''nQ!1(lI\ ' ate COf\$IOtlI Frocl>Oll e..creed UI'lChorIgo::! De<,,oed vetoes "'eo unde< c"","" Ii v.1 ~ coeceeeo-oe [, v I
a....,.",/IV""",, <J ....""""'"
Ponol
dooo
"'-Ia....,.",
lInMion ralel/C\eoIorc:e
",-.1C>al ~
Area unde< CuM!' [()foIl
pla teau
~
~
"(JrQ~'
A"""oge
1
"""""'"
Dow . lOaI biooYo.lobl'trl
COIlCeI'IIIO hOtl
[()foil
C1eoIOflCe • t~ JnteJvoII
" (II" lIlt' clf ( I i ~t ri lll l l i( m t1t'lx'll(ls nn billtlill~ to hotlJ p l'l\ lllOl pn 'h'i lJ\ und t isSllt' {''Ulls lit m 'llh . For u t l m~ wi lh a large' " ,luIII{' (> 50 1.),
v, · Iv v _ Iu,
3
w!lil., for d )11'0' " 1lI0) c'(111.'f \t"('i~hf « .')00 JiIOOJ(·) dn l~ wit b OJ s mall m lu llw o f tlistrihutKJIl « 11.2 I A ~). \ . h 'nlL.. to hI.' ind t-pt'mll'lll of (:h aJl~('S ill / 11 (Chap. 10 ). TI lt' \ 11}.<,,('(III(·1I1 t"ulIlplt'!i an' an;1l~7..t"(1 m illJt tlWM' n·laltom.l,ips. TIIt" - (·)'I·mpJil).· alt e raho m. i ll intri n..it., 1M'p'llol"l·lIl1l,ar ac:ii\i ty (im lut'fin n allli inllihi t in n ). h(-pati<.' hlo .. t1 RIM'. ,Ki i\(' tubular secrvncn. am i p l'l\ IIl'. p mtein h ill(liu /;:.
Indu(,1 C,"(1I11 jMrt,1 tn Illdt of Ihl ' contro l va lue. n ·f11"{1illJ: a Iai~t.(· r d l·ar4IK't·. TIli'\ ul""" r"'alioll is c,'on,i ~h'llt " ; 11. im luc,"ticm o f hC1latte.· .·Il~'lllc"S ; 11.., c,·I(~ar.tII("(' of a . I m~ of It'"' 11('fl;il k t'\ t r.K.1icJII rollin is 1·'fIl't.1('11 III 1M' "'::'n~iti\l' to d lallJ.:("!i ill ht· jla hM.'t·lInlilr ('n~1llatic,' ;...1i\;~ . TIll' (L da Sll~( ... t un l'fT(, 1 of rtfampln 0 11 warfa rin di ~trihu l ion . TIlt' ("'!ootim;th'tl \uIU lllt"!i of di ..trihu t:un . uhlaillt'll Imm CU I.. are U.lI' !J and n.l~ l A~ tln rinv; til(' c,"(lIltm l .tlU) rifa mpi ll pha-'>(''\. n ·'IM'l1i \ dy. n ll' s(' \-alllt'S an' p n ,hahl, · IIul si,l.,1JlihC,';J, utly d ifft·f(·nl. ( ' l1l)ll1t-{S )
OW'E ~
11
111
111l' IIlt'mp"'IIIil' l'(JIl~"( l ut'Il{'t' of induction can ht, app n'l1:t1ed [rom Ibe d iO'..-n-nce- in
th... n -sponse-t inu- l'II1'''''S, sllO\\1I in tilt' botto m ~mph of Fig. 12- 1. R lW}J{IIU t ' here is defined us lilt' ... I,,·\·alion in pmth nJlIlh in lilllt' ahow' a h'"<;f·lilw vnhre of 1-1 sec. TIll" II\l 'rall n ·spoll<;.t', !-orin 'lI by lilt' un-a muh-r 1111' respouse-tinu- l'III"\'(' aft N Ih... singl.., oral dose, is suhs lalliially n .... hu-...... 1 ill II...• pn ·<;.t·Il('(· of rifarnp in. Co nst"(Iu(·l1 tl)'. 0Ilt" wo uld ..·xpt'l1 under sh ·ady-slalt· coudtnous that Iltl' dosage of warfarin mu st he Increase..1 in the p rt"St..'lll'''-" of rifampin to main tain the sa nlt' prothrombm lim e. TIll" n -ason fur the app.ut"llily puo r l1.lrrelation between r"'spon~' alltl plastua warfarin concentration dn rin~ til(' first 4S h r after war[ari u uduuniv tration , wln-u rt·SPOll<;.t· is i!ll'rt'a\i llg a nd conceutratlnn is falling, is d i Sl'm~'( 1 in Chap. 2.1, T urnover Concepts. Hifa mpill is a known im llllt'r of IlI'pa lil' dOl~ metabolism. •md the ..Llta pnl\i d.....1in Fig. 12- 1 un- g"'lJN a lly l1msis!t' 1I1\\i th ind ul1ioll o f wa rfa rin lIlt't alxllisll1 by rtfarupin. II fl\H,\'l 'r. thcr..· an' p roblems wi th resp"'l1 10 Ille Int e rpre tat io n of IheS(' da ta, in addit io ll 10 ti Ll' aIXI\'t" ml'lltio ll('tl pro blem of rt-"laling warfari n concentration 10 rt's po nS(', \ \ 'arfa rin ts lIIit rlwlt.... 1 'l' a m('(' malt'. It s euantioun-rs 1m\"(' d iO'e n' nl all tk1);I~u lan t !x ll..-uci..-s a nd (liO''''n' nl kim 'til' pmp, ·rti,'s. Fu rthe-rmore. tln- dla ngl' iu prorh mmhlu h llw Is a l1J1lst"fIUl'Il(,' of d lan g:l's in sevr-ml d o tt ing (;1<10,"" Han :'maltos a re common ly used today, instea d of a p ur... r-nuntjouu-r . O m' Isonu-r Illay potentiate- or inhihit tile kine-t ics o r d)lla mk'S of lilt' ot l...-r. As lo ng: as ra(1'ma h 's a n ' udmiuiste-n-d, killt'li<- am i d)l ll:1. tilt' pe-ak ('(}JR,' ul ralio n (C ......) am i At 'C' an' t1 mmal it'al ly n .... ). L(' 't 1. althou gh then- is liltl(' appan'll t d l;l.Ilg:l· in 111(' half.l if(·. Tl u ~ ' Oh~·I"\~ll io lis . al first g:lalllt', app,,'a r 10 h e tncouslste-nt . Kml\\ing: Ihal this d m g is lIw lalxlliu ... 1IInly in tilt' lin 'r a nd olll'llll11t lling: (fn ull dose and AUC follo\\inj.t i.v. ad m in-
'mil
helpful 10 d t'fill('
20
fill:. I t- I , 11.., I,alf·lif., ..f ",,,,f a· n il , a dnll': "'ilh a ..........lr...1i..n Mi", ;• •h"rt'·"' ·11 am i d ..a ranl" · i . ill l...·;!,! 1 "'....." 'I l. IQ'I'''' (" 1" '11 n r-
o
cI..,,) , a , inlo:w ,1<.... (Vi rnw\lit) I.... flIrt' (l>I..J,; hIK' ) ;&I..J " hik' (..ul<Jl\..1
n ..I ... .. filWt..
"'lit I""" daily f".. J d;!,~., pri.. r In war·
farin admini.ttr..lw.,. n,.. I"~ol lUKI ,I"nolw. , of II.., t-It."'"lw., in tiM' pn.. thnllnl>in l inw ( ft" IX"'''' ' a ft' Ik" l... ~........l wi..." ri(;!,mpin i. ('< . . I"'ill· hh 'n ..1 (J,"">"f j:(f"I'I., (I mwJ . - ::S.J j.l M), UI,,,....I,,......!. ",ill, I"·n lli..,i"", fn" l1 CH t' '' I!>', R A.: 1111. ,.....111>11 ,,( ....h,Ul, ", dati" alK I n f"rnpi" , ,.... 'Ul. Inl" OI, ~l '-. ~ 1 :J.17_141 1. 1117-1 ,)
40 30 20 14
12 2
4 Days
O W TE Il 11
"' "-1,it. 12-2 .
1,,
""1"'..>1,... , I~ 1.. · "t"i~r"'il ..1 I,.· · " wnl I'no, l "t~ .. ",..rl<, ~1 t!;(f,.... , . ' " 1/.. •
I'l.., n~, " ....~·" l r-.. h.."
"'
0.1
·11
II,,· .lntl: j\ Io!lu- n " r..lt:-"(::!I n "' ~.l . I" '1 wi"·,, Io:iw.. h . (5 "'It)..\ ll'n·" .
11. >1 ,,~.I
"'....
I".....,
""\", i,, i'Ioo...-.:II ..·(..,.- (1)1;0<1
e , i ,\ '.: O.
"rah and III .L~."
li",...:..,._
0.01
1Il1" (" 010,,, ..1 j ,\ '.: 6.. ",;oil a po·ntnh, rlo" ..1 "'\on""·,, " f " Ml .01
I".,h ,,,...
'"l/:
(1 1tl1t/1. -
4 ,IlIJ M )
IF m ", _~ h;", . ( ;., l'l..r.h. \1 IKI " '" It,hr , c,
, rI,,'..1 'M'
~
..
),it,, 1.
Eir.'t1or ,,,.,,-
tI ..· ' h"
iti.."
or "I·
lm -,,,,I, ,I. <:Ii" . l'Io Mn ,-<:,I, T I..., ..
21,31fi...'l:.'! L ]<177.)
0.001
o
2
4
6
8
10
Hours
h f r( IIlt'1l1 ilclministralioll. is 1l("I'(II"I1 in tilt' p rt'st 'nl'" " r lilt' induce-r III Ilrl Mllll, ' lilt' sa nu - " ITt'(1 , as' IlI n i n~ all ;1(1i\'i1y n 'sh l" s "illl lilt' t l m ~. ;\ lp w llolol. likt, wnrfarin . is
E\.<1111p ll's o f t l m ~s that inllih it tilt' 1I1t'Ial" ,lis m ur IIlll('r t1m ~s an ' ~\ l ' n in C hill" 17, 111I l' r.ld i n ~ I ) m ~s . Ht'(lu(..'(1 IIlt'l illMJlislll can alSfJ I,,· a l"l lllst't IIlt'IIl'" o r IWPilti<' d ist',LS(' (C l.a p .
Ifi ), di d .u"'" d l' fid l' lll'il'\ . an d nt llt' r ("I II1t!it inllS, " 'h ah "'l 'r II\(' ruuw of 1I,'('no.<-", '(1 mt 'tilIMI!i{· 'l<1i\ dy. 11;1' kinr-tic ("IJIlSI'tIIlt'IIl..'s i1I'Ill.·1lt1 011 tlx- Il('patil' ext ract ion r.llin o r tjn- t1nl~. Lo w E 'l.In l l"li n n Rlltiu, TI lt' t' ITI"(1 o r t1''('f(';ls i l\~ Ilt'pal lll'l,lIubr a<1i\it)' fo r a d m ~ or low !I" Il;llit, ,'\lrad iull ratiu is illll'l ra h'( l by dala ror l·h lorJ'.m:azOlII· aml l'blonlia>'.l'I'Mnitil' .
C HAPTE ~
12
..9
T Ilt' concentration-tune p m filt' of tilt' muscle relaxant chlorzo xazom- in a subjl'd after a 'j!)()-lIlg oral doS(' is W I) ' diffe rent from that seen 10 h r after a single 5OO- m~ oral dose (If d b ulfi ram ( F'i!-t. 12-.'3). TIll' uu-au clearance- and half-life va llies we re 3 .3 mllm ilv1g ami 1.2 hr ill the absence and 0 .5 mllmilv1g and 5.1 hr in th e p resc nt-e of disulfiram . a se lt'{t ivt· iulnbltor of m:idali\"t' mctnbolis m. Till' cha n~ lI~ co ncentra tion of tilt' Inlulntor (a mi its lllt'talMllill' s follo\\i ng tht· sillglt· 500- mg dosc ) and the limited lillie of sa mpling ill tilt' p rl' St'lI l·t' of th e inhib itor preclude ht.'in~ highl)' queutttative. Nonetheless, the effect of ck-creased lx-patoceflular act ivity is ell',n for a drug with a low t' xlnK1io li ra tio; elt.·am.nl"t· decreases and half-hfe Increases . Another example is that of lilt' '1II,.iol~til' d nl g chlc rdiazepocde ( Fi~. 12-1 ). Its half-lift' is increased and its ck-arauce is dec reased ill pat ients wi th hepa tic ci rrhosis. Ord.! bioavail ah ilit\" ;1IIt.! volume of distri bution (110 1 Sh(1\\ 1 1) are unaffected. TI~at chlordtaa-pcode has a low hepatic extraction rati o (' V{' II in Ilt'althy subjt"<.t s can Ill' dt'tllll't 'l i From the data in the figun' if one also knows tllat the drug is ellmlnated primarily
_ 100
tlK. I 2-3.
'iE3.
~ ~m!tond dOM· I. ) i~ dr..mllh r..,.jh·
c
~
inl"1'\"lU.l..1aft.. , di." lfinun ,...lOIn,,·n l lei.
•• • ••
c
.~"
10
l>i...IIi,..m (.500 rng ondJ~il "!. K E. Mh)n .. J.• ;I'M.! I .iJl ih~. J.l1.: Sin.t:\t--
u
c
0 U
~
c 0
~ x
0 ~ 0
:E u ~
E
M o d '}".)
~
if.
0.1
3
0
6 Hours
~ " '"se . s
1
"
~ ~
. E u
c
40 30
~
:E
e
0.8
u
0.6
~
~
U
1
~ ~
." 0.4 0
to 0
f
~
I
~
.!ii 0.2
~ ~
U
0.0
~ ~
.'1,;:_ 12-4. c l.I"" liu"'p'''idt• • halfj, KTl"..... ·d ;oJKl tut al d,·aroUM't· I. tIt'l'n 'a",-d in I""'twILI5 ....;Ih l..-patil' ctr lif.. p
22 0
~
0
'2 0
Normal Cirrhosis
§. 1.0
50
." 20 .!ii
12
9
Normal Cirrhosis
~ ~ ;;
n ,,· pt.. ''''l lu M,,·nll1dinl1-
u"" , pn.fi\o:-of clJlonrl1Ul""' llf,..r . sin·
••
$
rho. i. """ "[';I n..ltc norm"l subjrth. ~Il"".ul ( ~ S E ~U and ilMlh-i
ncs
INTEGAAlION \MlH
'90
CHAl'TH 11
hy Ill'p,;,li l' lIIl'la holislll , tilt' h luud-plaMIl;\ U II ll',,'u trdl iuli mtio i.. di N.' In 1.11. mill ,,\'{'mg,' 11l'1l;llk blulltlllo\\' i.. 21) 1Il 1 /Illi l1/"~. III subjt'C.1§ wnb nnnnallll'pa til' flll K1io ll . t1K· 11t1};lhc (",l ml:ti ull r.,!in [CI.,IQII = (0 .5.'5 JIl I )rn i nf1,;~ )/(20 IIl lJm i n/\; ~ ) 1 i.. the-n " 'f'l't11't! In I I(' o nly
ahu lIl um u r I,...... IIi J;:h t:d nlf:t ion Ratio. n it ' 1ci1lt1 ic {,lIlSt' IIIt· IIC't·" flf inh ibitio ll of IIM'r.,It" li"lII o f a ( Im~ \\;111 ... hi ~h IWp' l!il· (·\tr.K1inll ratio 41.1'\' iIIl1..tn... I ('(II ~' tilt" (u,Kl m inistr.ll iun of dnlt'h· t Jillt· ;til t! I.,ht'lnlnl ( Fi ~. 12-5). TI la! la bcrolol is a dnJ ~ o f h i ~1 h' 1l;I!tC." ,"lr.K1 iulI rdfiu is , 1,'(11I{1't1 [rum ils dt·;lrdlll'('. 1.06 lA ir {t-sti mah ..1 bv d i\ idi u J: tht· i.v . ( 1o:1"ot" In " tlKo (um ""ll lflc liul: .-tee ~\ l'" in ti ll" arnck-L "ppm;.K·hin~ ht.palk' blond fill\\' and fRill; 1I.I').::I)(,wl · I.. I~I ' tlMI t.hdulul i.. (·limill"h.. 1
li\(·r. ;. lIcl 1I1'I M't' ~ lthjt "l1 10 1" II' min' fi rse-pa,.... hl'patiC I,...... and IJl"l~.u l'i.(· lIw pha mM(uIt ~c n .... iIL.... \\i l l. 11.(· drug. rather th an wi th ib 1I )( 1 ahohh~ . 11 11'" ' i.. a tllJ:t' iIK'n ' a ",' in AC C fo r lal w.'lok.1 wlwlI at llllill i ~h'n .. 1 e Jr.II ~·, hilI IKII ",1wlI ~\('Il intmH·IICIII..ly . in tilt' pn""'IK't· (If (;IIX'li d iIK' . This oh"" I'\'aliou i.. '·'I)("l1... 1 fn llc""iul-: in l. ih itM lII IIf IIII' 1,lilllill;lfw lII of ;l dm~ ",ilh a h i~h lM'p ali(' 1"lrdl1wm r.tlw•. 1111' lark of dMII~t' in ,m ';' follcMillZ i.v. Oltlminislr.tlicm n'fil"l1s IIII' minor (L."l'n·a.",· t'du",oc.1 bv l'i 1ll11i· (lim' 'ill 1111' h t11.,h(· 1·\Ir.~1iIlU mfw' ",)(1 ht' IM't' in ck -arance. t:\iCLt.'lItl~', MOI.I ReM' t.~mlilltlt .... In h mil till' 11l'11.Ih( · l'1illlin.llwm of Li))(101ol ('....e-n wlll'lI in ilih itilill llIl'(110. nl i.. wuu kl nol I",· "', if 11M' dl1:n..• uf illh ih itilill ",'n' ..IK·h a'i 10 n-d uce LaI .1nl ullo a (Imlot of u M·lll-patic.· 1·\tr.1l1 KIII m iKI. 11 11' la~t ' irK"n 'd \( ' in .-\CC folln",in~ nral al lmini..t ranon i.. a ('Im "'''I" I' IK'I:' of iIK'n';l"",, 1 h « .,t\ -ait .hilit\,; IlI' n ' ti ll' iIKTt'1II1'u t i.. " IJlJIII 56'1 , w h ill' 0 111\, a m in o Tclc"l'Tt";('io(" (:!U'l) W;L" \("'11 ill ti ll ' h;1l;lt it.· t"l mt1«1Il ran o. n it' tllt' rdj llt'utic ,urnild f) ' of till ' kinl·l il.' d "U l~("" in ti l(' prt"i.(' IMl· of l'inlt'l id iIM' is Iwi~h h' m,l ac.1i\ity of lollllt' llIlo l w llt'll ~\l'n nr.u ~" h ilt lIo t ",111'11 Wn ' lI intraw-uou..ly. ;K1 i\i l~' primari l~
AItlfod Blood Flow As prt' ''''' IIIt,, 1in (:t."p. II , d l ;III~I'" ill O~dll hl n ocl llnw ;llTt"l1 (·II·"r.1I1('I:' I IIII~' when t,,,trote.1 io ll mtiu is hi ~h . This t"lilld us iu ll is l lol-" "I 011 t1w l"lJlJl'l:'p t 11 pC'rfll.sillll .r.lt(,lim ihl.t io ll . It slMlUld IN' I. ,n lt' ill nund. !JnWt'\l'T, thai t' lT("l'h !;('"l 1ll(6f)' to all ;altt'n, 1 I»ltJl.1 fitM'. Il.Irt it1.lldrl>· ",11('11 t1' ''l·rt·;('l'l 1. lII " y SUIIlt' f';l'C. k' lw rfn sillll (llll .. id t'mtMllls ;lllIIlt' . FliTt' -. u llp le'. It cll'C.."n'iA.\t'C.l h l' JlNlll u'" liMy p nJl llll"t' lUlII\ ill. wllit·1i in h Jnl 1Il1ly llfTt"l1 lll'pat ul't ·lIubr ;tt1i\ i ty a l1l l l" ' lll 'l:' tIlt' ('\tntttin ll mlio . 1111· 1" t m(1 ill ll mtin ma~' ..Iso Ill' alt t' n oc.1 hy a d l'C. ·f('ll",,'C.I Mool.! flow
ur
AUC
. '1". 12-.\ . " "" ' ''II.•I..h'~ ;I"·h·,,,'''1. I,", ..I,...,..,,,... . 1o..w,..1 "" .i"nifi...... 1 (:\ .!'\.) d'''"(I'. .. t ..·" f> 1,,·..III,y h .. -n ...·n · ~ •." &e"
w.·,..
" ""II'
C J c .: n ..· ,·fl''''1' .. f "'~ 10"· \ 1.",·· "'.." 1r llF.\lO..· i" IIII..I" " , ' .., 1..1.1'"
pt m ... .li'.. 1.... K. J e l",. 11"". " ... " . I ~ :Yl1-4U I. 1Y'>4 I
CL
I.V.
80
,·,11.." .....
~ .j.. "'( ,10 ...· "r.Jh ' .. ... .. 1I .~."'~1." .10 ...· •• I. ·f",.· 11/.. 1,.., II..· f.." ,d, 'Lo:,of li " .. -1"I"..· I ,. ·..I II "l l ' '''Il: '''' 'n f> I,r •.TI"........1" ,,, 1 1..., II . 0(. ",fic".." ,
lui
Oral
60
g c
40
~
20
£ 8:
o - 20
~ NS.
F
CHAPTER 12
19 1
hl'('aml' t'n'I)' bllllxl n 's<;(,1 in tilt' o~all may 1101 pn l\itll' lilt, sallie t'xpos un' of 1111' dnl ~ 10 Ill'p al il' pa rt 'l 1l'h~ll llll l't'lIs , aud tln- p'ltlt'nJ of chstnbunon o f hlood How .... ttlun till' eltmtnal inl-: ory{an may d l
T. It•• 1 2-3. "-.......c.kl... tlc P. ,........ of Two Hypo....tlc• • D.....
"''''' '"
OlST ~WTON
""" l
H
•
III().l.VAA.ol8llIiY"
09 7 005
26 A30 ..
· ~ O:b "" , ful ... oc c~Iot""'I, ~_
'C_. ,._.,._'cJ~,"blood
CLE"'~ .",.,
6 77 ..... "'1..oo
"''''ON EJ0E1W
Wl/IoCTON lAl l()
~o
!-f'AIOC
.~
OW 005
0.0 3
0 05
0 05
0 06
.....
INTEGRATION WITH I(f\/fTlCS
CI-W'TEi 12
Intravenous Dose
0.1
Oral Dose
0.1
Drugl
0.Q1
~
g c c
0.Q1
0.001
0.001 0
~ ;: !l c
Orug l
6
12
18
24
0
6
12
18
24
c
<.> ~
2
0.1
Q
0.01
<:
.. .. .
.2 ~
0.Q1
···. .
0.001
0.0001 0
6
.. .. .. 12
..
0.001
Drug H
..
Drug H
.
0.0001
. ..
0.00001 18
24
0
6
12
18
24
Hours nit- 12-6. I,K-o·;o.....11>1,..1II<..... 10 11..·1i,,-, h.......,.,.. linl.· "fT...1 "" tI.... li"'. · . .... ,.... · ..f Il mlt I ~ ;O f".JrI~ ... I...M1...1 .\0.... 111'1 " , " p nlo.."'K 1d T 1 "" Dm lt II. ;0. hilthlJ d. -;o.n,1 ,Inllo(.
r"IIo:.....; 1l1: sill""" l.v. (lS-1Il1U ...,,1 or,,] (31IlJ""'ItI ,It -s. Ah.·n..I lili (· .. --l: ronnn.l ....... lili.... (--). 11,.. ;l.hsorphnn half·lif.. of holh t1nl~ is 1.4 hr. s.... T,.J,Ic· 12-3 fur uti pharrnamk illti il: P"'1)C'r1 it-s or th.....· Not> .In~ _
:",11:,- ,IiFT.·.... ....-s in \". iUt'S fur D n ,!: II.
Altered ActiY' ToMIar Sea,tioo FiWIrt· l ~ s!low!' tilt" efred of i llh ih itill~ tilt' n-uu l tubular secretion of alllm.killin by prolx-ncc id. An Increased A UG of a moxicillin is o ll.i o \ls; it rt· lIc"(:f:s a dc,'(:rt·a<;t· in clearance. Tlu - pn llllJl ~lIti(ln of ehminarion Imlf-lift' is also dlle' p rilllarily lu rt"CIUl'{"C1 elearauce: Ilnvolume of dtstnbunon (CU k) is changed rt'lalin' I" littl t', i llt l i {';tlill~ that p m h(·l\("C.i d doc's nut afft"C.1 the di stribution of amoxjcilliu. Til t' inhibition o r renal excre-tion ur this pt'llidllill by pmIN.'IJ('{·id he'c-'umes appare nt w!lt'll this pa th way is Isolated. HC'nal dt'ar,lIIl,{', that is, th e exert-non rate n-lanve to Ihe plasma conceru mnon . is d t'ar ly 1't"CIUl'{"C1 hy pmIN.'Ilt"C.·id . TIlt" substantial renal excretion of allloxk illin explains why a rt't hl('{'tl n-nal t:lt'ar.lI1('(' hus such a p nlllou ll{'("C1 c'ffc't.1 Oil total t'lc'a nllJt'{', 11l{' dt"C.'n·'l'i{· in rt"llal d earam'(' occurs bv inhihiliun or rlu- tubular M"C: rd oTY mechanism for umoxjci lliu, a dru~ that is virt ually ullhCll;m llo pla.sllm prote-ins. TI ll' de~rt"C.: or Inhtbttlon or this pml'('Ss is ma.sked by Ihe contrtbu riou o r filtrati on at ti lt' ~lo l1l{'m l ll s . lf seen-non is
193
CHAPTE R 12
Control
1.2
n it> 12-7. n ..· t-lt·ar.u K~· t;U "'·
f,......... in ~ a -I·min
" f Ii, j o-
1.\'. i ll rll~i"ll
"'0"'"
(3 ",~ltl i. " " 10...,,..1 t1,," ,,~ 1m..... (50 "'It) "r pm"r..'....... (-Il l
<> 't: 5
" 'It) ;w1", ini. lr..li"" ( ,, ' 6 hr 1 "2-1 hr , ...·f" n' tI 10..1 01 •
~ n"; "1t
0.8
~
u
n M...· olmlt" '
,uKI I" 1"'lil· " 10 1H.....-. lI"'I,"",a" 11I.....'..Ui' ''' h, - ",I.id, tI..· d . ·ar ,,· ;;11""'1:""" I..., n"I, " I, II mW] . - -1.3 "M ) (.-\' !AJ",.. I f" Hn
~
e zs
"fli."",'lI.i,,,·
~ ~ ~ ~
110
",,·n,af"' rl. -n·a" ·,..nloac,...,II''' 1
,," , I ,n" li 1\I linjt f,.. " "r
Plus Propranolol
C....,nocl. K..-\.. K~,·n. J.M,. FI,,10.,.·. 1' ,11.. a llol Kunoham. I. : I.i<".... il"· .·Iiminah"", Elf of l1I.ot.."n .1 a".1"f I'n 'l' '''' .1 eli". 11"' ", .1 n ,,·r...11:I3.1-I." ". 1\h1 .l
0.4
:5 0
100
~:;g:
'u -;::< o
E
-
Control
10 Plus Probenecid
~
~~ ~ " E ~ ~
-~
~
u
~
0. 0
u
0.1 0
2
4
6
8
Fl it. 12-'1 . 11" ' 1,1", 111" .... ". ·"Imh"" ("" I,·ftl. a,,,I I"'''l''' ,I,,· ,U'C. fill" .",,,,, iliUm i' ;,,,·n·;o, 1",f"1' .')l. l lll l>: ..n· ", 1"""i,r.·n~ I"r;.I1~ ill ".I"ti"" I" f", I'''1>: ~Il hjo. 1. ill 1" •• l'n.....II..· l ..... 'n,,1 ,,,...... 1,,,,,1..I ·IM. · 41>1 1 <1,1\ ,, ) " f Im.l..·"••i,1 ' I 1:. 12 lor ..", I II..." I lor I",·f" n· II,,· a" l i l>iI ~k ) . 11,.. .·1f,..1 i• •111.' 1"I,n",,·no.:i II . j...'I.... ",. U.. CI..,1..,·. II L . al1, l lI"rt,, ". It: A" I<,\killi, oI,·L." ,1.l" ic: .dol n,.· .·O'. "1 " f 1'" .1".,.......1J !u,li" ,;': n.l, <:I" ·"I<~ I ,, ·r.. 12:27.1-27.';' 1 ~1.)
(~)lIlpld, · ly h lnl:kt'll. n-nal dl ';U';1I 1 (~' u r Ihis polar an tih iotk is ('xpt 'l'h'l l to " a Vt' a IOWN limit uri ll . C Hi Ill'l',IlN ' it is lIut n'ahsurlll'li in rln- t ubule.
Ahered Plasma Protein Binding I\nm\-II'(I1--:I' u r (untlitlolls ill whid , lilt' h i lld i,,~ to pla.s ma pmtt·ills is ahen'll is cri tical to ptLSIIM t1 m g: rnuce-ntrutiou lIlnTlitorill~ (Chap. IS). \ \1 \(>11 aet ivities. rk-sin-d an d undesired. n-lan- tI, tln- IllJlll>lll ,d couceut mtiuu . d la"~t·s iu hi lld in~ di n -'l1:ly afT(-'l1: tilt' inlt'rprt'l;llio ll of total n lHl~ 'n trat illlt lb ta. 111i.s pr oblem ilppli(·s to t1m~s or l" lth low
CHAf'lU 12
' 94
Low E :-.lrad io n Ratio . C " a ll~(,s in t jn- tlwra peutic ....i ndllw of pllt'lI)'toin i t ' a fUlIl1 ioll of serum creanuim- concentrat ion , an index of renal function. is show n in Fi ~. 12-9.111(' h i~l1t'r tilt' r-n-atinim- concentratjou, tln- IUWt.· f is till' n-ual Iunct lon. The ' \i ndo'>'" falls 1",'(,.lUs('[u, normally aheml 11.1 , incn-ases tu 011'0111 0.2.5 10 0 .3 ill patu-n rs wt th S(,\,\' n ' re nal f' lIll1ioli imp'linne·lIl . For examplt-. gin' lI that lilt' u nhound ccnce-nt rauou n-qutn-d 10 pmtlul't· a ~H 'II re"POliS(' ill till' pn's('lIl" of n-nal di st,;('i(' is ti lt' c um- as thut ill tilt" a h""'lwt " it {" lInw' tl.al
•
fu · C - fu" C
whe-n-III ' and C ' aft' tilt' Iluhm llld rnu:tioll and Intal d m v; concvut rutkrn in tilt· prt'S('m, -' (If till' d i<w.';lW . n ·..pt't.1i\"d y. O il n·arr.Ul~(·llwllt
c -
5
COllt't'nlr.lho l\s u f 10 ,ulIl 20 lIlWI. in IIu rmal l'lJlld itio liS tilus hc."'Olllt' t'flui\'llll' llt tn ... ali( I ~ Ill WI , wlu-n III
(I"
n it. 12- 9 . TI,.. tl"" "I" ''' 'io- nn",· "r
1,1. · n~1"i" I",-", ~ I ,.., t"l;J 1'1.... " ... u'Un'lI· t ..~li"n , Io~'n'~"'''' "''il l. tI ..· , Io .". ~· " I' n'nal fu"d io..., hll l~o.i," "'''t. .., ""',,,,, n~II~' "" .
n " " '.,.·..''''i'..·. 1'" ,,,, t1 n. n..1,"'I W In ::!l l ",~il . n ,i. , -n i. a
"f ''''··
' l' . ',w.~'
"f n ~ I,w.,,1 1..,w.I IlI lt, I'id , i. n·· tiM' .....' · n l ~· "f l!..· n'n;J ,I'"'IL''' j I ",~ . - 4 n 11 \ 11. ( H, ~ I ...t \\ll f nu n fl."iI,..lmll: " f .In, lI:' I" j,Lo.,m;tl'n.. k in•. "" '" ~ \. ,...,·;011 .....; .. Z2fi,I I5- I:2fi. 1!l73.1 1..1,~lln
,,."'It.
,I,..·.. ...·
•2 o
o
50 100 150 200 SerumCreatinine Concentration (mgll)
CHAl'TtR 12
'"
" IM,lie (h lootl) d l'lll"lllll't' approaches Ilt'pat il' hlo odHe w ( 1.35 [l m in 011 aH' m~t ' ) ' 11!t· in l'n'spon 'ie a fte r oral udmhustrution , ht.'l~d llst· el. ll ot is 1I11c1 1'III~t'(l. Small Vo lu m e o r Dislribution. TIll' l'Ollst>fIUt'lI('(' o f 1Il1t'ri ng hillt lillg to ph~l1l a p m · tcins is illuslml('(llw clofilmm-. TIlt' lialf-Iife of clofibnc add (the al'ti"t· mat eri al fonm-d bv IWtlrnl,,·.;js of til(: i1d m inist(·rt'(l l"Ill,,1 es te-r, d ofih m le ) short r-ns From tilt' usual Ill.5 h r I;, S.7 1lr ill patie-nts ....-ith til(' nephmti~ s)lldrnlllt' (T ah lt' 12--t ). It is tt' mpling to mnd lldt' thai ll11'taho lislll (0111)" ll% uf clofibrtc add is r-xcn- n-d IInd langt'lt) is indul't'(1 and tha t t1t)sa~t' n'f lu in' IIlt'1l1s need tn I~> incn-ased in the-se pa tients. From a p harmacokinencpoint of , i t""" . lilt'S(' l'fmd llSio ns an- Incorrect . as 11ll' fnllIJS\i ll~ sllows.
~
u
c
"' ~ .=
-
1.1
• •
•
1.0
5l
- -z: Q
~
c Q
E ~ ~
o:g >1n i5
:5. "
..
•
0.9 280 240 200 6
t
B
• •
5
~
•
4
•
nu.
m"". -
• •
-~
..I1..r ;,,1111\1"" " " ;It!tnlni\1r.41i,,n " f 2t1 Ill". (h, the- ,,11... r " .ond. lilt' velum.. of ,li. lrll>" li"" ( ~ , tI ) ", It! II... half·lif.. ( 1I::r"l ~1 C ) .oK" "h· "·"'t~ 1 I" iI ...Tl·",, · wi'h ,m ill II,,· fr....' "I "" " KI, Id",-tit.· 1,,01..., ..... i. ""hd · pod...J f,.. " dml(.. . ,.......... I'n'1>r...",I"I. Ihal l. l' i~I)-' M1r...-t..d ill tI... I" ...r. (;Io-·"r .......· I., ·n· h I"·rf" . it,,, r.&l... li'n il....1. liin,Ii" " I" pi...,,,,.. pl'l" l<"in. ,10", ,...It inA......~ dMmu .... • 1" '1 ,10".... f_ f",of I"" , ..t " n... "f d1drll,,,t it"l ... ,,1. 1I"·n .(,,.... 1111" half·IJl;·. TI,,·I! "" ~ 1.... 1.....1 lito ">-1;,,,..... n "):l'1....itm_ ( I 3_~ J,l lol l (1).,1.. fn,, " fo;, ,,,.. . (: 11 .. ..,It! S1WlIt!. 1> (;.: Ili~IM .. lli< N' " f flrofl." " " I"I . VI: l nde pe nd e-ut .... ri..I'Cl u in " .....I}'••'~I ••(in'tI Lttlnjt dnlKt."Ot""'T,lr"'",," "' 101 l...lf·l;f,· ... a """nil of rLun... ,In'lI: I"'K I'''K In ", ..n , elin, 11...n ......0I. Th·r _. U4fJ.h'jUJ. iera K'l,n "Ii...~ ~ 1 "' ilh I"·nni. , it"l u f c .\". M,.. I,;,.)
li' ''' ..
• •
.' IR. t 2- IO. Tbe d" "r~"t... " f p r"p ... ""I,,1 ( ;r~," AI. 1........1 .... ibu"...~ ..'l r..h' ''' i " "'... 1.
,h .. 'd aw "r In n lfR'lot.. " ill, 11.. · fr..di"" 11"1",,,,..1in 1110-...1 of six ....a1lh" m"lt· \1 ~ u n h~''''
E
"' ::>
A
• •
1.2
•
3 0.D7 0.08 0.09 0.10 0.11 Fraction Unbound in Blood
C
ilK"""'"
INTEGAATICN 'NITH I(lNETlC5
'96
CHAPlH 12
c"""••,
T. bl. 12-4. Ro.. o l F",..c.I M• • ,..,re " S.nlll'l Alb..,mln, Dally ~1.I.. . lttl HaU.L1f. of tho Actl Fonn .f Cloflbra", CI.flbnc Acid. I.. Poll.... WIllI ..... With.",. tho N e p hrot ic Syndr . ... . •
..
.
'>I ~ ~I
CKA''''''''
,""'
CLE"'AI'£f
~ .,Al .... · . '
,
NephrOlic g roup
(N · 51 Conlfol gfoup IN - 81" "f..".GokI>oog,AP 113 17-125 , 19n
·0 ""
'IlI'
100 :to L4
1,3 :!; 0 , 1
1 2 :!: 0 2 ~.O J .Haa>.18
98
:!:
20
."'" ......
oo esc "'CO
:!;
05
".
13 :t 12
87:!: 35 165
44 :!: 0 4
..-de...n.n.l, JD e.:"...,.<J ddob""''''''' '''......
!XCI'fTlON
~,
101'"
13
~lfN
'"
:!:
0
47
...-c~'9¥-..........,
0<> ~ n0.-
118 10">\ .. """'-cJdo..O'-'<Jddbr"'oco:l .. O I I LfI,g. .. ~ ~ ...pn...., ~ O OJ .,...,. . I.xr>ot> ~ _"':lrqod
~.,
.. 000 ro-""'BonOI,tZ I. S Noooo,anc/P lo,b
<>'dW--"~ 1
,,"-Y""_Mo<~
a"'ed
~ . I i'ln.~oIo:>go<:b><J~.
IQQJ I
Ed.-.dn"AG
~
TW i al
In lIlt" nep hr otic synd r ome. there is ;III ('xtl'mivl' loss of pl. lSlIl;\ p rote ins into I lll' mi nt" whic h fl'SUlts in a tw ofold drop in se rum albumin. as shown ill Tahl(· 10- • . T Il(" Iullueuce of this drop in se rum alb um tn o nfr l cau he l'st ima ll't l From rl'alT;lII~t' IIlt'1I1 of Ell. IS (C hap. (0). TIll' normal se rum alhumin concentranou reported is 4.3 WtlL am! for do rilnk add III is 0 .0.1. Giw nl hal /"" , tln- fraction of available hil\(lin~ sill's unoccupied. is r- qnul to I, III(' vahu- (If #\/1 is 7.5 dIJK. AI a serum albunun couceut rattou of 2.3 WilL. tilt' calculated fml1io ll unbound in nephrone patient s is then
Iv -
I _ 0 .055 1 + 7.5 x 2.3
6
C lofi h ril' acid IIiLS11 low cxtractluu ratio ill thai its ch-arance- k ak'u lah '(! fru m k ' \') is 0 .32 lAir in lrealthy subjects. a \11111l' much smalh-r than llt'p;lIk' hlood lIow, S I lAir. :\ lth()lI~h oue miv;hl argm' thai hluod clearance is much largt-'T rlum pllLsllla dl'ara lll't· (also c/e" > I ). thi s is impossihll'. \'irt,w.Jly all drug in 1111' I M )( !~' is IMlll ntl to albumin (" = 0.11 1A g). Thus. plasma d m~ co ncentration COIll ollly h(, ~rl'at(' r th an blood d rug ('tllll'('niratioll hy a factor o f 1.7 (1/(1 - ln-matocnt), M'(' Appt>lId h I- F. With clofibric acid betng a I,,\~' extraction ratio drug. ch-amncr- is ('\1)('(.'11'(1 to illcn·,L'\l.' in llt'pl lTolie p atie nts. TIll' value o f unbound ek-arance , CUI". is 10.7 IJh r in Iwalth)" subject s. If otn- a ssumes the same un bound d t'ar.l lll't' ill uepl rrotic (llttil'nls, tlu-n d t'amJIl't', I II ' Cl." , in this ~roll P is (1.59 l Air. TI \(' volume o f dislrihutinn of clofib nc add , giw n in Ill(' f()(I!Jltllt' 10 Tahir 12-1, is 7.7 t / i o kg. This \~J1Il(' depends lit tle o n ('ha ngt's in p l'l\-lIla pr otein hilldi ng:. This is ",,'('n fmm Ihe n·latio lls!tip I-oI'IW ( '('1I \ ' ilm1fi' for a dm~ with a small voluna- of distrihution (Eq . 25 , Cha p. 10), namely.
v
II:
7.5 + Constant · Iu
Will. an apparent volume uf 7.7 I... III(' coustaut is 6 .7. IfIII is illl:n'a\('(llo O.<'L5.5, t1 WII th e lIppa n' nl volume bec o mes 7.9 L TIll" \-'Illum e unbound (\'ijid , 11Il\\l'\-l'r. decn-ascs fn nn 2.5710 143 L. 111(' calcularedhalf-bfe (0.69.1 ' VlCI. or U.69.1 · , 'II/Cl ..,, ) in Ihl' m-phroric peueuts is tln-n about 9 .3 hr. a \".1111(' \ 1 ")" dust' 10 tlml 011....·1"\"("11. S.7 h r. TIl(' two questions origi nally posed an' now an swere d. TIlt" hal f·l ift· is s!tortt' Ill"l! ill 1!It' nephrone pauents because- of dec re used hinding 10 album in; me-tabolism was nol illd u('t'(1. Unbound clearance was 1101 cbanged. and tl u-refon- no dlallgt· ill tilt' uSllal (lIlSing mit' of 1.5 10 2 .0 gltlay is nt'('(l t'(l in m-phrottc patients to p rodlll't· II\(' sanu- aW"'dgt· unbound l'lllK't' lltmtic)IJ in plasma . as ad lil'\l'(l ill pat h-uts \\itl l nonnal Sj'n llll ;Illllllllin. A sho rter
INlEGlI AtlON '
197
dosillg inte-rval (a llll l"(,rrt'spo lltlin,l?;ly sumlh- r mainh"n,uu'(' tim e ) m i ~"l 1)(' couskh-n -db e-
c..IU St ' IIf tlu- slln rk lll'l i half-lift' , 111l' l"('lIlhinatinm o f l"(md itiom and s o-nanos in dnl~ tllt' mpy
M ('
multitudinous. This
chapn-r hiL\ pR'st'lIlt 'l1 «pp r oaches and e xamples tnwun] i lll (,~r.l ti ll~ kinetic pri nciples and physi ol l~ l' l"(lIIl,,("p tS. T o l,,( lInplt'h' th is iu tl',I?;mtiun, Tubh- 12-5 summa rize s tilt' (·fT"l"ts {'X I)('(:h'l! From incrt'a.'it'l i ('n 7.)"III{' ild i\; ty. inhilut ion of 1l lt'Iahlllislll, decn-ased h1uotillow , and ill('n 'ast'll ji, in bioI 11.1 for
, ..... 1 2-5. AlltlclfMrIetI.tfecb ef AlferMI••• I. Seledetl PII.,.I.... ac V 01. 11.1 Se..Iy ..,.
•• V.rI_. Pa_
Dr.,••
fH~OGICV ~
tNCJfASl'D
9APM'f lf ~S
~Sl""'llON
,""W
oe
06Sl' ~"'TI(;lf'6
""fMTv"
low In"ow","",~
001
H<>p::ll, C
HoIl-·Me
I'
AUC (bloodl
1
-'>ON
'"
.... l "'ecVi.....
E..'roc Otl 1()1,O D,,'9
. U_r
enec
OlC IlE~D
0000
"""
N:IlEAStD fUCTION
weoc-o NOooo
BlQ(MJ,lobol,!y
AUC (bloodl H,gh Hepohc I ..nooco ~()rlo [),U9 Inltov<''''Ou~
001
Ho ~~ ,1e
I
AL.!C ll*lod)
t
... I
BoooYOllabillty AUC (blood)
''II > ~l boldr.og>
" """""""""'""".• onc_
booonoei ........ _ _ .....~
0/
"" _
<J>OoiQb,l... ei~b •. d--""'''''9
1 <:Io<:...-l _ I.... O/",,~ "'"'- <:10<:_ .. ~~ '. ~., boo oq.ooIy"""""'-'l boo 0 ~_ ,n ~'eo
STUDY PROBlEMS IAnswer$ 10 Study Problems o re in Appendix 11.) I . U st 10 t'xam pll"S o f physi() I' ~l' \
H~h
HIgh HIgh l~
l~ l~
I.'
CHoIo.PHi I2
.1 . FigllTt· 12-11
~ lll l\\'S
plasma d m g: conceut mnou-tiuu- pmlih-s
r()lIu\\ill~
ural atlmillis -
lratio ll u f I\\U d nl,!:::" (hull. d nl gs an' d illlill alt 't! I'xdllsin '!y by Ilt'patil' llIet"ho lism) 1I1l1 1t ' r the- fo lltJ\\i ng: ltm d iticms : I J IW t'xt nu.1 ioll r auo. 1'1;l-" 1II01 protein h ill(liu,I.t is : normal k uo w :\ l; lIiIIH '(! (l'a~ ' B. twofold in e rt·a ...• in fit): am i <10111111'(1 ({';.N ' c . twufold t1t'(n'il'>L' in Ronl1", Gmp" _H igh c' xlnu.1illll ra tio . Tisslw hilli lillg: is: I\lITlIlal (l'a'\(' A): 1'111\1.'(1( { ';.l-Iit'
Ta" Gm,,'"
II, twofold jllt 'n ' ,i.\( '
I").
i n Jil T);
and dClllhl('(1(e a se
c. twofold d t '1.'Tt'l L'it ' i ll j ll r ).
Altered Binding to Plasma Proteins
Time
Altered Tissue Binding B
TIme . "IlC,. I 2-11.
Draw II\(' {'u rn 'spolld ing: t illl(' profiles of Iht> unbound {"t)llI't,'ul ralioIlS for till' tlm '(' situations ¢H' II for ('ill"1. uf lilt' hm t1m~\. Be sure that (Oad. ~ru ph show,; ti l(" salk-nt
CI-tAFlEl/ 12
'99
INTEGAATICN WIlH I(INETC S
featun-s i lldlldin~ n ·J..lh1.· arens under Ihe curve, peak umos. and half.hves. 111t' "01nun-s of distribut ion of hoth drugs art:' ~rt:'att' r than )00 L ... . :\ 1t 11fl1l~h rl'<'1~liZt 'tl for lI1any )1.·urs. rln- interaction l..·tW('t·u allnjlunllnl. 1I>;('t1 in tilt' tn-atnwnt of J.:0llt, am i fi-nu-rca ptopu n ue . an allt i lJ{"()pla.~tic aJ.:t'III, wa... 1I0t wt'11 1111' d,'rstood nnlil tln- kim-tk-s o f Iht' Interaction WR" elucidated. l1 w ,\lIe vallies of l'inu-n-aptupn nne- 11I,fon ' am i aftt'r pn·tn·alnwlll wit h allop uri nol ( 100 1lIJ.: o mlly Ihn't' lim es a d,l)" for 2 days ) f(lIlo\\ill~ oral and t.v. ad ministmlions of (1.1; nuuole of f).. nwn'aph 'punm' an' ¢n·n in Tnbk- 12-7 , Botl. drugs an' nlll~t1y elim illilh 'tl h)' nn-tahll!i SIJ1 in tln- liver .
..
'."1. 12-7. Ay._•• Area. U.tI_ th. PI••_ 6.Men.P"eP-rl_ Ce_••"..,I...·n•• CUrv•• I.....I......,. ..... A..... AII.".rI"•• ."..tr•• I.......
.....
Si~l ifk~d.lltl)' dlaJlJ.:t'tl h)' allop urinol treatnu-ut . For 11.1' pU'l xJSt· of this problem . 11.<;(' 11 blootl/pla srna eonee utration ratio of n.6. a . calt:lIlatt· lilt' dl'ar.U1l1· anti hioa\ ailahilil}' of fi-mereaptopu riue ht·fore and 'lftN alkrpu rinol , h. I'rmid,' a IOJ~ktll ktnettc explanation for the enhanced t·flk';.I(')' of fs-nn-rcaptopuri min til(' prt'S('IW(' of allopurinol. 5 . Tlu- phunnacokus-tics o f U1.-thn'O-llwlhylpht'lIidal t' (Ritalin) shows ('llanliost'!t't1h i l)', Tah le 1 2~ sutnm.mze s the ohservatlons aflt' r Lv. (10 Il\~) and oral (-i f) m ~, immediate rl'le,l\e ) dust's of ( + )- anti (- )- i~O IlW rs .
TIlt' half-life of f)' l!len.-aptopu nue was not
, ..... 1 2-8. AUC ..... H_H·Uv I...,."••••••"d Oral AtI.I.I
MathyI...... ltI...._ ••n A..... h.,.rwte
..
IN1Uo,tNOUS 110 '"'111 I.
~JW
1-)6CW{ ~
B9
60
·Adopood ltc:n s.--. N ~
........,.,. PIo..,..n~..
~SC>".·U
lAB
AUC !JJ.g h,/ l) HaIH,fe (hri
~,EO
36
120
57
15
39
~"'"""'d~ ..
101 4·11 1<XI3
Cnlculnn- tilt' fullo\\i nf; for each isomer I , C lt·arJ,llt't· 2. O ral h ioam ilahilit\' 3 . \ '0111 111(' o f di ~!nhutioll b. !o.lt'lhylpllt'lIidatt' is gi\l.'11 o rally, Bn efly di st'Is..~ tln- dilTt'n:'lIl't"S ill ah~o rptioll anti dispu~ il ioll o f tlll'<;(' two tsonu-rs. e. ( ;iwlI th at Ihe kinetics of t'ild l of the- iso me rs is 1I0t alTl'<-1t><.l by the othr-r. cst tmatc til(' approxi mate isomeri c composin on (ratio of amounts of (- ) and ( +» of abo so rllt'1:l m.l!enill t' nh'n n~ tilt' S)1\tt' m k- ei rcula tiou . Do yu u t·X!x"<.1 the ra tio o f the isomers ill plasm a 10 dlan,gt' with time? Co mme nt bnefly. 6 . A tim?: highly lxmnd to plasma p r otein s ifu :::: (J,O l) bas a volume of di slribulion of 2"'0 I jj'O k~. Tln- li\l.'r is the on l), organ of el iminalion. 111t' hepatic ext ract ion ratlo is lUI.') dl'~ pi lt' the fad th at Ihe Fractio n in blood that is unl xlIIlld,ji,,, is (111)' O,lMl.'; . 111t' hepanc hl(xltl Rnw ls "l1 lAir. ,I ,
NTEGAATIQN WITH KNfOCS
200
Ct-lA.PJER 11
a. Est imate tlat" vulu('s of til(' f()II(J\\i ll~ paramet e rs fo r t his d n ll{: hllMMJ dt'a nUlt'(' (CJ.h ), clearance (e Ll . volumes (If dtstrtlrutkm h;(.......1 0 11 d m j.( ccmenn unous in ri a-slim " 11It,,, (\',1) and in h ltMld (l'b), and half-lift·. b . In uremic pali.·1l1s til(" volume o f d ist ril m !iull 0111(11111' Iraction uubound in ph\lllil . u\'t' ragt' un L and (UJ3, I't'Slll'(.1ivd y. Is then- any t'\ide un .>lhal tlu- un-mtc sta te alTt'(1s tln- tissue binding? If so, in what tlin...-t ion ami by wha l Fadm is lissllt' hilltling
I".
ultt'rt'tl? c. \\111'11 th is dnl g is in fu !it"tl infm\ 'I'!lou sly al tilt" sanu- tl ms la nl m it- In it 1l;llit' n t w ho is and hits 1)('('1\ Tt"t't'i,;ng another d m g. the " 11m ' o f ji'l, is 1I0W Icund tu Ill' O.fH. Unde r stt·;jtly.s tall' 1"lll\(liti Ol\S fo r bot h d m gs. pn-dict tilt' ml io (If lilt" Illlholilld <:0 11rr -nt rations of t he dm~ ill tile prt'M ' ll<.'(' ami " b M '!I<.'· of t h~' ot her d m ~. f.
Ampicillin ha.. tilt" f(}lIowi ll~ lI.\"(' m~e phamlal'uk int'li(' pa nUllt'tt'r vallll's ill a 70-k~ sub, j~"(:t :
F(om ll • 0 .6
V = 20 l
Ct '"' 160 ml/min
Ie "" 0 .8
Ddl'nnint" tilt:' minimum orulmatnteuancc doSt, of a mpid llin. to h~' ~\'t'li ("I'l'I)' 6 hr, to keep tilt' u rina ry d m ~ l, mn'llt ra tio ll (in Urt'f('rs) aho\"(' 50 IIIWI.. Tl ns value is tilt' minimum inhihitorycoucentratiou a~ainst an alltihilttil'-n'sbtallt tlrga nisllI Ik,lil"l"("t1to Ik' p n kill dll~ tilt' !l
Prett-_I..•
.1....1....lllty, .~. . .Ic a-_...., .... 0-1 AVe ..
P~TlI S
B;oo-.oo,labil.ty (%1
Cleorooce d lV minl 001
A~ lmg,tlf/U
27 ,t; 2b 1 (X) ,t; 006
2 1,8 .... 26
46
:!c
4<
138 ± OI2< 27 8 .... 100'
111t' a uthors SIl~I'st t hil! a ll illl'rease in 11t'jl
INDIVID UALIZATION
VARIABILITY
OBJECTIVES The reeder will be able to: 1. liS! six major sources of variability in d".1Q response 2. Evoluatewherhefvoriobililyin drugresponse iscouMK! bye VOfiObil,lyin phorrnocol.inelia, pholn'lOcodynomia. or bolh. given respcose and phorrnocol:.ineti<: dolO 3. $lole whyvariabilityaround rho mean and ~pe of the frequency di$lfibuhon hiSlogrom of a po1omelef ole as impor1Olll as
the moon
llseif.
4. Explain how variability in beccuc enzyme activity monifem j~1 in variability in both phar· mocokinelic pCllomelefs and pIoreau p1a!>lTlO drug oonceolmliOf\s fOi' drugs of high and low hepatic ex"oction roses.
5 . Sugge$lon opprooch lor inilial ng 0 dc»oge legimen for on individool potenr, given potent popuIorioo phormocoltinetic
dota and the individual's eecsocbe chorQCfefiylO
Thus far. I)l(' ass umption Im... IIt't'1I made-that all p('()plt' a rt' ahk e. T rue, its a species. human s art> rt"l~m ahly lJ(ml( ~t>IU'()II S . hUI di ffpn'lWtOS a 1l1 01l~ pt·opl p do exist indudin g tln-ir r espnllsiv("IWSS to dmb'S. At'(:(J nlillgl~·. t1lt'rt· is a Ireqtn-nt llt't'(! to tai lor d reg ad mi uhtmlion 10 the Individual p ath-ut . A fail nn' 10 do so can h-ad 10 im'lTt'(.1 in 'lllt'ra p)' in some )lalit'lIls am! to ocitv in otlu-rs . This S{~'Iioll o f the hook is de...o tedto indhidual d nlJ.tt1wmpy. A bmat! 11\" J\it"'~' o f tlnsubje c t is p resented lnthls dlaptt' r, E~idt'JI("\' for alit! causes of vartatkm in d rug rt~POlIst', am i ap proecbes toward i lld hid llal i7jn~ dn l~ I!lempy an' t'xaTllim"ll. Subsequ ent chapters deal in much gree te r t!l'tail wuh ~t' lwtil"S (C hap, 1-1 ), alo::l" an d wt'ilo::ht (C hap. 15 ), tliSt,lt'i(' (C hap , 16 ), iut eracttons ht'lwt"t' n dm w; within Ilw hotly (C hap, 17 ), and IIItmilorill,i: of pia-una ccncentrunou of a dnJ ~ 01.'1 a ~ Iidt' 10 illdhitillali7jn ~ t!m.l: tllt' rdp)' (C hap. I Ii ), Ht'fon ' prot't.'\'\lin~, a di stinct ion IIlIIsl lX' made hl'lwt'1'11 ; 111 imlhidmtl and th e populalion. Consider. t'.~" tilt' results o f a sludy dl'sip u "Ill o examine the l'(m trihn tioll of an acmv tlist,01.'it" 10 varia hility in d n l.l: rt's ponst' , Suppose. of 3n pat ients studied during am i aftt' r n'covery, o nl)' 2 shll\\'("I1 a subs tantial diffen'lIl't' ill rt'SI'ltlllst'; in tilt" remai nder tilt" d iffNt'lIl'(' was insibynifil'llllt , \'it'\\'t'(.! ,1-'1 a wl lolt" tilt' d ist',l-'i(' wfluld nut 1)(' couslden-d as a si~ ntficaut SUUR't' of \'ltriabilil)', hUI to Iht, IWfl afft'(.'It'(.! Il;ltit'nls It would. ~l o R"t I\'\'r, 10 avofd toxici ty , Iht, t !()sa~t' R,;nlt'll o f the dm" llIay 1lt'1"(1 10 ht , ll"(lul't"t1 in these two patit'u ts during Iht, disease . 11l(~ lesson is dear: A\'\'r.l.l:e d ata an- useful as a ~ Ji de; hut ultilll att'ly, luformation rt·rtainin~ to th e imlhidual!l;i1il'nl is all-important , 011 a sim ilar but broade r pomt. substant ial di fTl'n'lIl1' s ill rt's!'ltmS{' to most dm~s ("xist ;l lll{)n~ !);,Itit'nls , Such /" tt'rind hit!lIal \'llriah ilily is oft eu n -llected hy a \'llrie!)' of marken-d close strengths of It d m~. Because \'ltriilhili~' in rt'Sj'ltlllst' within a subjt"Ct (I" t rn illtli\; t!ual) is ~t'nt'ntl l)' much smallt'r than jrlt('tind i\idual vartaluht y, oncv w«'1l-t's tah lb llt'd , tlu- n - b 203
..
,
VARlA8IUTY
CHAf'T E ~
1J
mually little Ill '("(! to slIhs('(IIIt'ntly adjust lila i lJ(li,i dllil]"S do sage rl '¢lIIl 'lI . C lear ly. if i, .tm in· t1hi dual , "anabilit y wert- l a~e and uupn-du-tahle, tl')in~ to lilmh- t1l1Sagt' for all lndlvi dual wfluld lit, an l'xirelllt' ly diffi cu lt ta...k. partkularly fur dn l ~s wirh narrow thera peutic wi ntlows . St ah'tl d ilTNt'lltly, a t1nl~ t t.al ('xhib ih a hig l. i"tmimlhidlla l va ria hi lity ill pha n ua(~ )k i lll'l il'!i ( 'ill I lit, pn'S('rilM:'t! only if it h ,l' 11 \\1<1(· tln-rapt·ulk window.
EXPRESSIONS OF INOIVIOUAL DIFFERENCES 1-:, ; 111'11('(' fo r Inn-rindlvidual di !Te n ' Ill" ... ill dnlg n '., )xlIls(' ('1I111('S From S('\'(' ml SOUrt '!'s . \ "ariahility ill till" dosagt· n-qnin-d I " produce a ¢H'1l n ·'poll....· is iIIuslm h 'l) ill Figurt · 1-.'5 (C hap . I ), ",hid . s!lows t jn- nidt' ran g" in tlu-
The Need fOf Model. TIl(' IlIaJ!nitmle an d n-lat ive co nt ribunon o f p hanml(,,(lkillt'lll-s ami plmnllal"lKI)llitlllil',. to \"a n ilh ilil)' in n.'sl'IC)II'il'!U a ~\ 'l' n t1osaJ!(' wi thin a patu-ut population \ '01 1)' \\i t h th e drug a m i. 10 souu- exte-nt, till' co m litio n hl'ill~ t rea ted . Fo r example, wil lt a uonste r oldal antl-Inllammatury d mJ.:. tln- rl'!ati n ' contribution of pharmal,,(KI)llamil' \' ln a hilit)' ma)' 1)(' different when t ht· e-ndpoint is t he n-lfcf of a lu-adaclu- th a n wheu it is tilt' rl'! it'f From chronlc iwilt·s ami pain s a.\sol'ia lt"(l \\i l h illfla n u't l joint s. In d inil',,1 praet ice, all t' m pts 10 a.s siRJI the n-lative (,,(llItrilmtil lll to pha n llal 'flkillt"tll-S and pharlllill'f){l)llamil-s lIlay '"" mad t' ha.s("(1 O il di n-ct ul l'il·rva tions of p lasma ("( IIl('('lltmtillll an d rt'sl)(lIl'il' , 1111' lL\sih'l lllll' llt coukl 1)(' s l n lll~I)' InHm-nce-d. hOWl'\- t-r , hy till' Ii lIli ll~ of till' ohS('f\-ations a nd I lit" lIlal?;lI it udl ' of the response,
100
75 HI:. 13-1.
T ln- . ..~,. "f l1<·u",m,,~ ·
." 1 1.",,,1 ...ill, ti nH' aftc" an i.\·, 1.,,111, ,I, • uf lH l4 "'10<~ ,I<'....."ri'lln I" " .... IlI'n h ' ·...lil.,...' ...·k ( I mJ.il-. - ll ij' Ii\ IJ \ \ IcOI Iifi< ..1 rn" n ~-hrn ill.. \"D .. F;"..II.'r. Io;. ·l ~' . J.. " I. >lI· D" ni
c.s..
,tI,.1 (; ,.. .. ·1... T i l.: Pup uLol il. ' 1'1,an " .......~'};u nM.., o f .I<........' nni n , C hll , l'l.,m n,om l, TIlI'r ,•. 'i2 :."j2~').16. Im .l
~
~
0
'""
50
~
" ~
c,
25
o
o
80
160 Minutes
240
320
...
CHAPTE a I J
as Illustrated in Fi~ , 13.....1. Here. a t1m g that displays htth- iutr-rpatient \~driah i l i~' in e...... t-. a nd in maximum efTI't.1 . h ut J a~t' vnrialnlity ill hitlf-Iift and concentra no n nt'1'(lt't.llo produce 50% 1Tl...xhn u m n ' spuIISt·. is ~H' n OrdUy at 1\\11 tic lSI'S. Onto that adlit'\l 'S d ost· 10 maximal rt:'spo nse in all pat ients and oUt· that dOt·s not. .<\ t ti lt' hight'T close. Ohst·n. ltiuIiS millie at C_. wo uld SUAAt's l litth- va riahi l i~' ill e ither (''UlIt'(' n l m t io li o r phan n a('otl~lI;lI n it"S . 'Ai lh pcrhups a g n'a tt' r a.SSiIQHllt'llt of variab i li ~' 10 I"t' fo rm er. "'0; va riation in pl a.sma couceutrut ion p m d ul 't' s n·lalively liltll' dmll ~I ' in rt'SrNlIIst' . AI later time s after thls higllt'T o
dOM'. su bsta n tia l va riab ilily is uhst· r'\1.'t.! ill INJlh l't lllt1.·l1tra l iu lI a m i
rt'SpUUst·.
99
••
20
50
Q
ilE
•
z~ 10
o
•
•
•
•
./
90
"
~
••
B
A
30
In cont rast, fOT
•• • ••
••
•
o
0.1
0.2
0.01
0.3
0.05
0.1
0.5
Plasma Nortriptyline Concentration (mglL, IOQ scale)
Plasma Nortriptyline Concentration (mgll)
.111:' 13-2. A . TI,,· pI"" ,,,,, pi".",,, n"K~·n l r.llic", "f lI.. rtriIN~IIlM· \;trio-s ...i< "·I~· in 263 poh... 'h n,,-...i'ill~ lt n ~"K'II ..f 25 n'R ""rt ril't~"il>t· "....t1I~· th · h"' ,L.il)'. H. Th· n"K~·n l r.l" ,,"" " '!o:"">mlaily clioln!>" " ..!. " r..,,,, 110.· ' Inal"" l I"............., 11K' 1"..n llli of 11K' '11"",LtltW numl>l·f "f polito" t, ..... l..nU....J ou f'"~,jl "",,un,t 11K' "'!o:;(ritIUll .. r II..• "">t~ .. 'lfll.li"n _( I ",!:,' I • • 3 ,1t IoI M l i H, ~ l r~l' "' OI l •...k~ 'lltl ..d rromSj" 'l'u l . t-.. Bt"}ta . ( ).. ;uK!0 011<'. ~I.I . E. : t"UIKLt" K·III.tl, nf d"'i...a1 I'I>;(nnOOl' .It~ . In [) n'j(T"";(lnK·nl. t:.Jit...l b). G .S. ......" . E. lmlMu'l/:h. Cln",-!lill lJ 'l"lC'l<>lK·. 197" , 1'1'. 1--11.)
•
• •
••
o
••
•
•••
• • ••• • ••• •
2
•
• •
••
•••
••
4
•
6
Unbound Plasma S-Warfarin Concentration (J.1g1L) nil:. 1$...1 . Th· ""J,<MlI,,1 pLtt... u ''OIK~·ll lr.l.l i,," .. f d Ol' pn~l"min...lt·I)' acti\'t" S· arfarill "" "'I(;"h·d ..., 110 a \Jmil". dt1/1t"-· nf Itllllt.~~,t..I""' , ,..rit", ...;. 10'1) """ >1'1/: ll !U''' II' .. r 3.'i 1",,1" 'nlo n...... ~'in~ mk' """rf..rin, ( I "'Wi. - 3,,1 11M) ( "'d" i>t.~l fnltn <:1""11. t: ., ~kl _·I,L.i, . ." ,J . I','lCI{. \ 1 . Madu,y.'" I) " (;1..... R, R.. ;UKI Rt....L . KI. ~L l)i' p,.. ,Ii"" nf ",,,rf;inn .·n...lltic......·n ..", I n><1...h"I0"... In [""Iit..'h ,I" n" fo( nmltiplt· '''"inl/:. Hr, J-e lin. 11""01." '01 . J7,5fi.~. I""
B
CHAPTH 13
''''''''"''
206
15
1 0.75
10
large Dose
0.5 5
0;~
c
c
0
~
'"
~ ~
0
~
0
u
c
6
0
'-'
12 Hours
18
24
ee
E
'"
0 0
6
E
12 18 Hours
24
.~
:;
0.08
'"
0.1 5
a:
0.1
~
c
~
Q.
'"E 0
0
2 c
0.25
0 0
0
0
0.06
~ ~
Small Dose
0.04 0.05
0.02 0
0 0
6
12 18 Hou rs
24
0
6
12 Hours
18
24
"' ;J/:. 13-4. n ..· into-,.;,,,I,,iol,,...! uri.t"; I ,~·I " " " Il'l' n lnd iu n ;l,ll..1 """p'If'''' w .nt'S " l I t, ,I. "tII.I Ii" .....( ,~",·n,.li< .. " st..........n· pi.." ,,., " "... ·nlr-..ti<.... I" ·ftj . ".1 (ri,,1I1l (,,11.....; ,,11: ...~•• ,KI ~"...Il tI ,,( IIdru!!: ,I..., .Ii.pl~, 111110· inftorl'"tit 'lll , ,,riahi hty in C-. . I_ "Ill,1n...\im um n"'l'l "'~. hod Ltr,.:.. Inl"'1"""'n l ,,.ri.. hility· ' " l...Jf.!>ft. ..",I ..."..,·" 1..-", ..,,, 11••• 1...1,,, p"_I,,,,· ."ill'l ",..>,i ",,,,,,"...,. . ..... ll i ~ 1 [...... (l" p l: ;o.l '-.. llw llIouitlium Inal l 1);'1;'-11" i. rn"IoK. ..1 wit h li ul. · ,-..n..hilif:.' in ,';Iho·r C _ , .,. 1'Mp' " " '" C ..... ,,·. \'",,.;..,"li l,. ' " n .." ....'I ..-..tit .. IUIlI " ,.. ""•. i. ....·n ..' td .-, Ii"'.... I ~." .k....· ' t."U" m): 1<1 1_ •. \.. ri..JMlit)c' '" C_ i. " ,[110,\.... IM,I th.., in ""'1". '''' i. 'M ' " .".iI.·.
"""I""''''''
""'1""'....
Ill(' IO\\'N dos" . a ll ~.,.. then- is slill liUIt' inh' rpati('nl va riah ilily ill C........ bu t IIUW rhr-n - is l'tlllsitll'rahll' \'ari;lh ilily in rt'SllllIIS(' , nib (1I'lx'm ll' lIl't, nil dmO(' sud tinu- in tlu- ,,-~si~lIllt' lI l of vari;lh ilily is lIliuilll i;r.l,'t! hy t" p rt'Ssillj;?; '"
DESCRIBING VARIABILITY K III l'\\;Il~ how a particular parallll' ll'r varies wit hin th e 1'I
CHAf"E~
1J
20'
VA/lWllUTY
lilt" thn-e IIHlolllt't il~dl d m~s s!lcMn in Fi ~. 13-5. 11\l' mean, ur central tendenc y. fur all th ree d rugs is tilt' sa me. hut till" \1I.ri
.listri""l""'"
H K. 13--3. .\ s lho· fn ~ lt .......,.. f..r II..• d.·..,..,,,.....f Ilon I,~l""llt'1 k;oI.lru~ (A, B. C) .1......,. Iii••• ;"'I.'r1.ItI I t.·fin••~...I''ilohllity an . ,,,,1 dll"' ""'IU' ,,,..I ll..• '''''1.' " f II", f....I'IrtIl'Y .h..r.nl. lllun .~IT\....., il ,. ,.. ,t.·filM" lho· fTW"" it .. ·lf.
A
c
B
c
Clearance (arbitrary units)
20.
VAitABlUTV
OWTH 13
WHY PEOPll DIFfER 111t" n 'a.'i01IS wily pl·opl!· differ in thelr n-spousiwm-ss In d rugs ill medici nal pn xlut'h art' manifold and include, i ll ~('lll'ml on k-r uf importance, ~1 ·lll'lil.."' , t1i "t';l \( ' , "W', d nl ~s ~\'(' n l'tml'(llllilalllly. an d a \'aridy of cnvi mmm-ntul fact o rs. :\ h holl ~h i ll ht'rilslill a] dtsonh-rs, alii) o!l lt'r d io;(·'lO;("5. 11lt" modification lIlay ap ply In Iht" t ! m~ ht'i n~ used to In-at ti lt' specifi c t1iSl'llo;(' but may apply t·qu all), wf.'l l to other d m ~s lilt' palit'lll is rt"t"t·i\;llJ.':. Fo r example, to pO·....-ut l''({'t"!lsi\'(' accumulation am i Sl) reduce tilt' risk of Im;itily . tilt' t l usa~l" o f Ihl' anlih iolit· ~1 'lItam ici u lIS("tl lo In'al a plt·uml in fl'l:tioll uf a pali t'nl must hi' rt'l !LI(''l! iftl lt'llOllit'lll also has compromised renal funonon. Sim ilarly, hypl·rth yrtlid it· patients rt'tp lirt· hiJ.':Ilt'1' than usual closes n f di ~o\i ll, 1I d nt~ used to imp mn' cardiac emtit' nl'y. \l on 'tlwr. a mod ifi(';llion in dnSlI~t' llIay arise nol on ly (n lln the tlin 'l:t Impairment of a di st·'L\t'd o'X.1lI hul also Front s.t'(.'(mdal)· ('\"t'llls that lI('l.'tIlIlP
T."•• 13-1. A4WltI_I.___. K_ _ .. c..mt....... V.ri...lllty I............. A maIO' penl ed"'0100n.
'ood
Pot;enl r~ con \lOry on changing The roulE! 01 odmiOl~llotl()(l Not only pIlormocoi<,roet>c.s 01 d,ug bu4 a lso meIOboI'lE! concenIlO1l()(l~ can change ~'"" ond occo~11y edenl 01 o~P',on Ofe oflecled by eat'ng EHec~ depeod on COlT1po$lltOn 01 food 5evet'e pt"oIeon rtl$lfodoon may ,ed",e The '0 ,"" cJ d,ug melOboIiyn Drug el!ecb Ofe ohen ~ "' w.oler~ and WQf~er5 oa:upol,onolly exp«.ed to peshc;de$; a ,esuiI 01 enhanced d.ug melOboI'$fTl. [),u,nol\lO'1Q\l()f» Ole Ioeefl in phormoco'.,netlCS ond on d,ug re~loe The!.e effects ho-.oe beeo suHl(1efl1!y ,mporlonl to Ieod to !he deYeIopmenl 01 a new $i.lbted, chronopi>ormocology Clol!.e requirements oIloOfll& dlug~ d,f!e;o between p:ll,en l~ liv,ng ,n IO'M'l a..d in
!he cou~"'"
CHAPTH 13
A wdl-tlt'sig:lI('(l forlllulation d iminislws tlu- d('!-'Tt'(, HI' \1uiahilil)' in rlu- n -h-ase charact e ristk-s o f .. tim}: it! t"i Ul. Cood Ill all u fadu ri ll ~ pracuce. wi th careful contro l of the p n K't·ss \"lui ahlt,s. r-nsu n-s tln- mauufact u n- o f a rdiahlt' product . J) nl ~S an- WVt°n l' nh"mlly, topi("ally. pa n 'lIlt'rally. sun ] hy inhalation. Houte of u dnuuistration not only can afft"(1 tlu- con('t'utmtio ll loeally am i s~~h' lIl il~ally hut also (";11I alh' r tilt' svste-mic concentra tion of IIwlah · nlite l'llln p,m'( l wtt h thai of drug (C hap . 2 1)...\11 these- factors (',11I p m folludly lIffl"(1 till' rt'spo liSt' 10 a ~iVt ' n dost' ur n~ lIlt'lI . FIICItI. parti('ularly fat. sluws g:,lshi(' 1' llI pt~i llg: lind so decn-ases tilt' mh' o f dm~ absorpHOIl. Oral h ina\"ailahilily is not usua lly alTt"('It"t1 h)' fond , h ut then' an' mall)' t'X('('ptiolls to this start'lIIt'llt. Fond is a complex mixture of chemicals. {' smoking h'm ls III reduce d ink'lll am i toxic efft"{is of sonu- d rug s. illd lld ing (· h lo n l iaJ'~·I'1tI\itlt'. d iaJ'x'p am, and thl'llphyJlitw . TI l(' d m b"" alTl"{of("t1 an ' t'xlt'n si\"t'l y 1111'1al>. ol i J'~'1 1 h~· Ilt'palk' o\i dalillll; iml u(iiun of til(> dm ~. n \t"taI M,Ii J'jllg ('1I~1 11t·S is tilt' likdy (·illlst'. \ 1au)" 1" 1\i n III llwnlal p"lllltallts l''{ist in hiRllt'r ('{lllt'l'ntrations ill lilt' lily Ihan in IIII' L'tlllntl')'; tllt'Y (',Ill alstl stilllulalt' S~l l l l lt's i s til' IW[Xllk IlwlaIM>li(.' t' n ~1 1ll's .
Identifying the Sources of Voriability III p ral1i('{·. aH tl1t' aIMl\t'-l1wntiollt'(l fol(i u r.i ('an ('{ltltrih uf(' 10 ohst,,,,,'tl \t., hall(!lt'(l plll'nylbutX'JlIlt' mon ' slmdy Ihan did Iwalthy sllhjt"(·ts. E\idelllly, Sllllle of till' olhe r dnl~ n n 'i\l "t! ha.\ t('11 pileI!' \ IIJlltiVJlIIt" d im inlliioli. • Varions slrah -git's (~1Il hI' t'mpIO)l"tl to id,'nti f)" Slmn'('s o f \
OWTUIJ
2 10
A Normal
90
..
...... .-.. .....:. :•
"• •
70
•
'. ·1· .•:
~
50 30 10
Disease
No Drugs Drugs
.
•
•
Normal
• 197 • 162 • 144 • • •
130 110
B
Hepatic
J
55
..:.. ..• ...... j.
• ••
....
. .'••.
---"-
'
" ...... ..
:;~
-.'.
~
;.
~
w
--- ~
'<
~.
•
••
."o ' ,:t
l' • •
'n •• • •
No Drugs Drugs
. 197 • • 162 144 •.:• • :.. •
130 110
Hepatic
Disease
'.
... .. .:.
•• • •
.:::
.:i: -,:.'. .... ,'"
.e.
30
·
10
95
Number 01SUbjects
36
19
34
61
Number 01Subjects
"".e. 13--6 ..\ . :-.;.. t1irr,·n· 'It~' i. .....1\ 1 1\ , h.' ;t\1·r~· I ...J f. lif" "r ph.. ,,~lh.. toon....· (hu rilJ.u ,;d Ij".· ) in Ilnn nal " ''''''''' 0 (Iot" ''' IIt'' ''Io) ~ I Kllh"l in I"",w-nl ilh t""P'-lic.· di..•.....• (u ........ 1 puinh ). Ii...\flr••.,wrllhn ,K ' 10, ... • " , ,,,,I<.. ,>lIlt·. ,In,lf' {lIltl,! I.. ~ "h l f.." " ' h....· ,,~ .., .1.. ".., (,Ltrk I t.. " P" .....,I:'.. I .. h,nirwli(,,,. S.. ;",.1Will".·, . n,: 11....,,11..'1...........· 1tJ.. 1 i",,-
,'U",.).
IIiv.i<1 ""·I..IM>li",,ill ""h,·,,"
"';110 li..-r ,1;...;<... in
...l;1Ii"" In pn"i""" ,Im l: ll ,,·r..,,); . 1,;",,,-"f1. 1: 127.'5- 1279. l ijf;.'oj. l
all o!lwf f act ors Slid, as agl', g,' mlN , otln-r dru gs. and did should 1)1' he-kl constant. TIlt' idt'al 1.I., 1II1d \1(' a IOIl~ l udilml l·m..s-u...-er t1t'SiP l in wlik-h t'ad l p"til'nl ;I<.1Sas his or he r own cout ml. Th i.. d t 's i ~ l is often nol pnss iblt" hos\, ·\t'r. TIll' pa ti('nt 1.I.; t1l renal d ist'lL'>t' is Kt' nt·m lly not a...-ailab lt· for ..tfl(l~· prior 10 tilt' dist';L'>t', and n -ua l dh,';t'it· is gl' m' rally ir n -ve rsjbl e . T Ilt' 1"II'11t's am i rt'lilliring lIlallYd nl gs, indlld ing the mn - or intere..t . Can' mu ..t ..liIIl ",· taken, howev e-r, 10 ensure thai a suffidenl 1lI 11l111('r or pati t' nts an' ind udt'll with t·11l·1I or !llt' at tnhutes or condiuons of interes t .
DIFINING THI DOSI-RlSPONSI RlLATIONSHIP \'ari a bil it~· h;t\ an impo rta nt I",'aring on the " ,,",il1U1t/tlll o r dose-response n ' lutio nships ill clinical trials. " rxunmou p-oe-dun- is 10 t1hi dt' p.llit·nls into St,....vral ~mllps. t'at:h gnlllp n"t'!'i\i llKa
CHAPTER 13
'"
till" I. i ~h - lind Inw -tlost, group s (111I han ' tilt · sanu- ph sma conce ntration (mul n'spoll s(') . nault'I)". Ihost· in tilt' !o\\l-tlost· gn lllp with a Inw cleumnce and thuS(' in the hi ~h -t lost. J'n mp with a high dt'anlll t't' of till' d m g. The overallef fect , by i ncn·a.~ i n g vari;lhilil)"within t'adl J'n m p , is to weaken tlJ(" lIb ility to dt'lt'd : a do st"-rt'spo nS(' n-lat ion ship. Om- solutiu n is 10 inl·n ·a....• thr- 1I11 1111)('r of suhjt'l1s ill each gn lllp to n-duce til(' uncerlainty of estinmting tlJ(" IlW,Ul n 'sl:M l1Iw at t';1t'1l d USt, It·...d . Here. tilt' p roblem is Oftt'll omof 1I0t km J\\ing in ad\"ant't· 1Im\' ma ll)' slIbjt"(·ts \\1.lIIld II(' m-cded in till' trial . ,lS \\1,11 ,lS till' mldt'll t·xpt' IlSt· of an incn-used uuml x-r o f slIhjt'l:ts. Anot he r so lutio n is to {'XptN' t'al·il p;ltit'lit to S(...r-ral deN ' 11.....· ls of ti lt' drug. 111is I,lst solution has the di stin ct ad"'lIl1tilgt' of nut un l)' im·f("Lsing Ihl' chances of ('s tahlishing u doso-response n-lat ionslup. h ilt :llso of pn)\i d ing an estlman- of inh''1'''llit'1I1 va riahility in tln- n -Iat lonship. Unfo rtu lliltdy, ill p rae· tit'(', Ihis dt'Sigll is not lIl\\-d)-S pussih lt" ('spt'('ially fur c1 m gs for wh ich till' full t'ITt't.1 nn l)" occurs " fiN several months o r IOIl ~t'f into d m g administrat ion. A thtrd solutiun is rlucono-nrration -controllcd d inim l trial. III this approach. tln- pharmac okine-tics uf lilt' tlm g is fi rst I...-aluuted in tilt' pa lit'nt cohort am l tln-n, b'L\.t'tI 011 th is iufonnation. dUSt'S anaeljllstt't l !itl Ihal tilt' pl;lS Ill ~1 conceutmuon in ('adl patient lit'S in OIl<.' o f st''o"('TiII l i~ll t ly dt'611("t! ba nds . This mort ' t·laho mtc , and !it)IJlt'lilllt's mon- expe-nsive. "I's i ~ 1 t'nablt,s Illlwh d l'art'r stah' lIwllb to 1M' IWldl' ahu lII Ill(' t111ll't' lIlmtion- rt's l:M1Il!it' n '!alio nshi p and about Interpattent \1lriah ilily in phannal'tlkilll'lit's , lI uwt...vr, it lIlay Imn ' limil t'tl utilily fur tllN ' n-comme-ndanons, if a poo r corrr-latiou is fOllllcl IM'lwt"t'n plas ma d nl g rmn-en trution illlt! Tt"SPUIISt". ~ I a ny orlu-r t11 ·s i ~Il" . ... al)i n~ in t'tllllp!l'xil)-, t'adl with llc!\1I11tagl'!i and duadvan, t;lgl'S, can 1M' t'll\isa~t'Cl. III all t.'
KINETIC MANIFlSTATIONS Conside mh le \1lriahil ily ill t'llz)"llIalit' adhity am i, to a lesser exte-nt, ill p lasma ;1II11 tiSSllt' bindi ng exists t"''t'll ;1II 101l~ Il('altl.y iml hitluolls. II nw SIKh \llriahility man ift'sls itsl ·lf. ill pha n mlt'tlki nt'l il' paTilIlU'le rs ancl ill such IIIt'
212 . ';l( - 13-; .
CHAP'Tfl! 13
Fi" , t..·",h t,~ . " I".·.: h
~,
0:'('(1"..1 3.il l
10
Inl: 1I " ",1o~·1I " ..· ",..ll~·. in ..,ju' " ,,, , 10" ,.I i"; • . 1" 11/:<, hIT.·n 'I . .... i n ..u r ..n- " u. I.u' ill ".nl r... , ,.. pn >-
B
I'r.u" oI.d <1" 1: l ~ l , ,I,,· p ~ ( ·IIlnd i.. " . an,;d· " ....., ilJ.·IIIK-al. ·11......• ,>l ·",..li..'" a ;a' "'1101"'1,,,1 r... ,1,, '(," ,~1Iu .... ;, ,Iml( ..r I. l"l\;.'h.: ,-\' r...1i"" 11M! i~ ''''""11,,,,·h· " ""'I"I... li",,,1ill ,I... ti\. -•. " " ri ",trill !)' ill I..•• 110011(" "11'-::-""" ..<1"11~· i. mil.n1 f, ,...1 pri",an l:_ ;n . 'aria·
6
1II,.J.·.or..,tt,,' . a,,,II"·'It'(·I lf·llf.-; lit. , '''11:1.1-('('1" f tl"'''plo},!tin.- h •..Iah"·~- " "",..,,1. (I m l hil\;... -.uI..I,ilily i. (.Jo ..... In UX l'l ill all " ,I'jo'th . ..,..II.............· al"" '] >li,," ' . ... ' m ..IIlII" ·t, r,..Ito. tI,.." ..1;"'ill.
r.·(·,...1 ,-"1,,,,11' .. ( ,Ii. lrihll ti""
•
4
,...... 11':' S, T' M'''. I- '",,,,al ,~", ·n1l.Ii"" • .l
2
•
o
B
16
24
Hours
du'>t's In produce - tIll' Sl U III ' I' IT~'(1 , us might 1)(' 1111' ( Mol-'i(' if tilt' tlnl ~ is 101)(' 1I'\('d il-S a _'it"(latin ' Il~l)Uf)lk UT In r~ 'lil '\·t' a IWilllad w, ' h l\\'{'\'{ 'r, if ti lt' d nl ~ ts intt' ndt't! for chrmuc 11M', til(' dt'gn"(' o f \',uiahility ill an'mgt' plateau cooccnmuton sho uld 1I0t 1)(' illlw n '1I11)' diffi-rent From that whic h ('sish lilr a dnlg uf Inw Ilt'patk d l'armlt'(' am i h a\i ll ~ till' Soillllt' d(~ 't.:' of v h ¢n'lI I ~'
c
...OV
•
F 'Dose CL· t
t1l1sil1~ Inn-real. Fo r a dn l~ of high Ilt'patic ch-arancc-, \1lriah ilit)' in C .....n,lIl '('h m riilh ility ill 1-1l ~ ' 1ll" adh·it~· thrull~h F: wln-n-as. fn r it dr ug of I(l\v hepatic ch-aralll'l', \1l ri a hi l i l ~- in C...... n -III'(1s variahility ill 1'110111(' lId hit)' t1mmgh C/. (wtt h F Of I), In hu lll (',lSI'S the- oral ( Iosill~ run- (I)(t'\(o/t ) \m uld m-ed to 1)(' lIdjuslf'(! hy III,' sanu- d ~n"t' to maintain a eommou C...., wit hin sllhjt'!:1s. Tl us is adlil"\'{'!:! hy adj lls l i ll~ IIIl' doS(' for the Iti.l!:h.d l'a mll('t' ti nt !!: (a.. h 'llf·lif(, is rt'lati\'dy constant l and pcrhap.. hy a nuxnm- of adjll.s t i n~ do 'it, and dosill!!: lnn-rval (¢ \l'1l Ilml ha lf-lift, \'aril 's) for tln- low -dt'ar"dnl,(' d nl~ . o f major importmll1' is Ill,' 1lll( II'r1~ill ~ variation in l:"IIZylllt' ';' ll"ti\i ty, whid , t1ifT,'rs Irom o n,' l' nz:,lllC s)"!'tt-m 10 another. ()h\iomly, In miuimizi- variutjon in pharm ';'ll'llkilwtks . moh -cuk -s 'l'{ l\lld m-ed to 1)(' 'Yl ,lt'('h,, ! wluch. if IIwtahnl i;r.t'!:1. an' substrat e-s of " IIZ\llU' svstems Ihal show Ihl' I",lsl va riahility alllOl1~ sllhjt'(1s. Un fortulIatdy, current infon n;;tiu n i.~ ins uffil"i" 111 tn make tI,i.. st'!('('lio ll.
wln-n- t is tin-
~
A
250
0
~
~
'"
VAA1A6lUTY
CHAPTEI113
100
~
U
~
0
_
~'§, !> ,,0_ ~
e
50 25 10
~
E
5
~
~
0
2
4 Hours
3
5
6
7 B
~
250
0
~
\1",,10:- ,>
100
~
u 0
I' i... I..·••hll~ i llhjt-e.1' •.• -1, n-. (I ll mp;""'r 10 r"ill!>l,..1 ur al l.· (.,., "'10 0" .. ,...nol.. ,1lT'. ..."', . 11..· pl., ,,,,, ..11........lr..tio"·hm.. pnrlil. " "~'n- , ....,' " mil.., r..Ik_ inlo: t v. . 1",in i "ill, II... hou " ",h" In 1.., ...liI: rlU}ll'" _ 1I'it}· .." ....,I.! t h",," "lIp i' 11I,," ift'lt f'(1prim,;arily in ,..,;. ..hilo t~ i" "na! hit.." ul..hihl} (16-tiO'll. ro.ll..-r dUll ill . hIT.·,, ·....~ ...in d .· itr.....-e ( I I / min) "," it~, I, r- ·rfll'it .., r..t ,·.li",il.~I. " r I..,.......,,, Io..lf· llf.. ( I "'11:-'1.• • 3.9 11 \1 ). (1I,..lr_l' from s l...."I. IH : .. ;.;,...1 ,,11•. 1-:. \ 1,. .....1 ();d .'I. J .A.: rLt..,,,u 1'. ... 1',....."'" 1... .. 1. ill . 1,,[.., ...111, . 01 .... ......l it.... in f. .... .-I,i"I .. ·" . (;1i" . I"",r,,_~.I . 11..--.,, 11,1121;!l:1. 1!J7fJ, lu l'" . I,K...d "'i ll, p,·n niu it.., " f ( :,\ '. 13-Ji.
..
~
£
~
.'l~.
n·i,,~ I I'"~,r.....,j,.1 Lv.
_
~'§, 50 !>,,0_
25
~
e
~
e
10
0-
E ~
5
~
0
1
2
3
4 Hours
l ow Clearance
5
6
7
High Clearance
6
" lp;. 13-9. Ear-d ...1 poLa..m.. .Iml:. •~ .... ~~ 'l llIlit ..\·lirn. · rrufilr" .1"ri,,1t .. .11Il'ln~ illk,...,,, ..I st...ad)' ....to· f•.IIt...·· i" " .-ftrtl"k" 0.....1 . Imioi.-t....tit..' o r ;<. .In,l:,; d""" ",.. in lic .. ,l7)' .... _1,,·· ll~ fur .. . 1011/; I...."'~I . .., Ih.· ..., -II·.Um...J n.... 10:-1 "fht1..,Iit.· ..I" "i ,,..IiI." .
6
~
a
1>t'...
~ E
~
u
4
4
2
2
~
a
'-' 0
~ ~
C ~
E
~
"O
c,
0
4
6 Hours
12
0
0
Dosing Intervals
4 6 Hours
12
".
CHAl'T E ~
13
It follows From tilt· ror('goill~ tim! then- i ~ lUI iuhereut n ',L\ UII 10 1I(,li(,\"(' thai a !it'! variatio n i ll (' !l 0 111t' ;lt1 hily (caused h)' a variation ill ( "Il1ll't'lltmt iulI of t' 1I7.pm·s . Inhil utors, Of im llll,('rs ) should ('1IIIW a v;n 'aIN i"tmifl( lhitlual variatioll in pharlllitl'uk illl'fic pa r.lIlwlt·rs . o r in C ...... for a t1 mv; of IliV;h ht'!l;llil' (':\!nK1ioll than fo r Ollt' o f luw ht '!l
DOSE STRENGTHS I'mdlll'" an - fn'f I Il('" I I~' markcn-d ,lS uuit do.....·.. uf dd illt'fl sln·II/-.>111. sud . il\ 50 or 100 mv;. O h\i nus ly. i f tln- t1wmpt·util· ;11111.'\ is s ufTi d t·utly wide-, all !liltit ' nl s can " "('('in ' the sauudo">(' stn ·lJ/-.rth " ll1msl irn ·spt'(·ti\'(' of iU I~' diffen-nces in ph 'lOllill"llkillt'til-s alll llll V; ti l(' pu tten t pu p ulat ion . A narrow tllt'nllx'ulil' index I\('('('ssilalt·s the manufactun- of !it'\'t'ral doS(' sl n' II ~ II , . I Il ,wl'\-N , A lt hllll~J. till' Huaiuumbe-r of , In 'llh1hs t'ho'WlI dl'pl.'lIIls 0 11 1ll,1Il~' pnK'tical issues. 11 n lll~h t'!>.lim" It' u f Iht, numbe-r can lit, c alculated ill Ihl' follo....; I1 ~ manner for t1 n l~' Intended for dm- mk nlaill h'llalll't· IllI.'ntl l)o" SUPlll l"l' that till' maximum am i miniuuun d l'amlll1' \"alul' s Ihal 1.' 1ll't)lII l);'l"~ 9.'5'1- uf till' jMlit'l,t Ill'P" I,tti, U1. I lt'si~loI h'( l C l ....... du d Cl ........ n" lll ''(:t in· I~· , di fTt'r by il factor t.f , i' , TIMt h . C/ ,....., "" fi · C l. ",m. It \" l11 ld then follow Irmn tilt' fami liar f(·latiomh ip F · Dow t
•.
- ct . C
~
2
tlMI lill" riU'~1' of dm i ll~ rates IIl't '(ll"l l \\1lU ld hI' sh foltl if IlIl' objt'l'l \\~..., 10 obtaill tlU' sanuC.. ,... ill all pa tients . In p raet ice-. till' therapeutic imh-x is suffidl'utly \\i dl.' lu allow SUnil' toh-ram x-. I.l"l an'ra~t' plate-au coucentrattons wi thin :!O% o f the cptunal \"<11111.' lit, al'(:t·pt . ahh-. "\ (11 )n l i ll ~ly, 11ll' hi~llt's l dusil ,~ m il.' th at ('tm ltl ll(' ~\"t'll 1011 p" til'lll \\i th a d t" \T;Ul('t· \·alm ' of CI..."" is om' lilill p n lOJ Ul't.·S it e...... tl ml is 1,2 tiIJWS Ilw ..p lillllli ,"111m·; tl w 10"' '1's l d mill ~ rail' tha t could hL' ¢n'll 10 a pali l'll t witl r 11 dt'i\T;I1l('1' of C l.....u is mu- 111011 pmtlll('1 's a C••."' Illal h U.S ttnu-s lilt' u pliulill"1llul' , 11.., mn~(' of ,lssnd ah '(l dO!'iin ~ r.111.'!'i (and Iwllt'1' umounts, if lilt, dtJsill~ intr-rval is h 'p l (1J1lsliml) is fourfold . :'\ow, IIsually. adjal'1'1l1 tlu.S(' s trt '"~" s di ffN b~· a factor of 2 . Tln-refon -, ill IIII.' current ccunph-, if IIII.' slllaIlL·..1 tlOSt' s t rt · Il ~ 1. is .s(l 1l1~, it would 1)(' n-asouahleto market 11 1n"t, doSt· sln'nj.,tths, ,'j(). III~, 1U1I'1Il ~, ami 2f.l1l' 1Il~ p mtlll <-1s. whidl wo uld sliffiL'l' for !}''5tl uf tln- populcnon. O f ,hl' uUfs lalldi ll~ St,l,. t!lusc' wit h a pa rti<-11lilrly h i ~h clearance lIIay he 1Il'lllTllIll()(lall'( l with it Iargt'r-Ih all ' IIs' I;I1 matnn-naruv doSt,. (lllllp ri sill~ it (lllllbinitliu ll of th e market ed unit IltN ' strengt hs. or 1 11I·~· lIlay n'(1'ht' it markelt"C.l do St, sln'Il)..'lh mon- fn'( lllI.'lItly. 111tJSt· \\i th a pilrtklllitrly Illw l'!I'aTiUI('1' \·011111' 1l 1i1~· II(' ;lL'1'1 l11l1l1tJtI;lh'(! hy t ak jn~ tln- ltJwt'sl il\1lilahlt, dt N ' stn 'lIh'l ll II'!'iS fn '(IIU'utly Ihall m llal , "t"C.";'IIISt' Ihl' llillf·l ifl' ill Ih is ~n )IJ p is likl'ly to he tI.., Illn~l'sl in Ihl' Illlpll iitiio li.
ACCOUNTING FOR VARIABILITY It n 'mains III ht, !it't'll how inf"nllal io ll 1111 \llriah ililY (";.1Il II(' 1J"l'(1 III d l'\i St· all optimal dtl'oil~I ' n,..rilllt' ll uf 11 d nJ~ for In'"lnl("ut of a tlisl' il"l' in an illllh i tluitl l);,llieut . Oh..i ous ly.
tl u' t1l'sin"C.l " hjed iw \\1mlel ll(' lIIos1 l' ffid ently m:h it" ,'(1 if till' indhi dual's de lSil~l' n '(ltlin'lIll' nfs ('1l1lld l)(' <'";.lk11Iah '<-11H.ji'n' fltlm lnhlnt'l/! 1111' tlm!!.. \ \ 11ile Ihi s idt'al <-"allllni he tot ally nll'l ill pm<-1il1', SC lllll.' ' lIl,('1'SS may II(' adliew"C l hy atlupti ll~ III(' ftllltJ\\ill~ lnll, ' of ilppm.wh. whiell a ppl ies wllt'll all palil'lIls n'l jllirc.' lI.t' , allll.' (n nhtllllltl) pl.t'ma l'1J1lL't'nlmlio lJ r.1Il ~c . Tilt · a ppmilc:h is In Illm l ' fmlll till' popll lilliun pha rm iKllkilleti<-' par.IIII1.'I('r lostillla h'!'i 10 the illtih i tillal palit'n l's \1III1I'S.
'"
CHAPll R 13
111t· firsl sh 'p is III i tlt· lIti ~.. tilt' mos t \-ariabll' pa ra lllt' ll"r within lilt' patieut population. Va riabili ty ill tln- various pharmacoktnenc parunn-te-rs within Ihl' p' llit·nt populatkm in the 1·~tl'lIt of first-pass los s. as !Il1'lltinllt"tl p n '\i ullsly ( Fi ~. 13-li). Fur ol lll'f(lm~.., such llSt111'tlphyllim·. tilt' only sub stantial va riahility is in d l·araml ·. \\'ilh ot lu-rs. am iIJlI.. rune and plu-nvtoin Included, si",tnifiellllt "lIriahili ly exists in all p;mmlt'lers. Fillilily. fur some, coustdemble variilbi li ~' exis ts ill pl.o mu p mt" in hinl lill~. 1II'.\ t step is to t ry fu ill'-'tllllll llKl!k . IS much of tlu- variahility :IS pos-sihl" with mcasuruhle d laI'Hl1l'ri.s!il'S. If tlu- d.dml·tt-risl ic is di slTl'l l' allli iJlllt' llI'm lt' nt, thi s m il Ill' "dlit'\ l-'C I I,y partililJll ill ~ I l lt~ 11IIpulali till iut o sulll)(lp lllalio lls. Fo r example, us Illustrated fell' clearuuce- ill FiJ.:. 13- 10. if Ilw d h t:n 'h ' d laraetl'ri sties are IlI'plt!ie di Sl: a_Sl' and smu kill).,t. tlu-n till' populatkru wll ll l tl l ~· tlhi tll"tl into Iour t-;l ll'J.:o ril·S: thuSt: who s moke alll ilmn' 111 1 I.l'pa lit· t1ist·a<;t·: IhoS{' who sllln!w and haVt· lu·pa lk tIL"";l"" : thost· willi Im\1.· lw plltie d iSt·.t.st·
n il'
T.bl. 1 3-2. DetI Sp.clflc DI........._
V.rI...lllty I. tho 0_1 AJ._.,.tI••, DI'p.slt lon_ and ett-_•••th,. D_g' Wlthl..... Po tl.nt Po pul . tl o ...
v
lltlJG
.AmiodofQfllill
+
Cyc~
+
a +
+
+
+ • • +
+
N /A
+
+
?
+ + + +
+ + + + + +
+ + + + + +
Dtgo>cin ~
~onAlo
....
++
Ph&noborbtol
+ • +
+
+
~n
PJcpolloiol Quinidine
Salicylic cod ~~
+ . + • + + +
++
Fill; . 13- 10. 11,.. (n" I'" "''''' .li,lnh"u"" n( d.·a r..nw " , tlo;" tl..• I"tod ~1i''1, t P''I''',l.otit", ( - -l i ..
,, ,
,
, ,, ,
.. ..
,, ,, ,, ,, ,, . - ... y, / , , ',,
s ...
Clearance (arbitraryscale)
f", ..1it." " f II....1."1'" ,,{ tl..· {n .. I' .......,.· .h..tnh"!i ' .. ilhill tl.., , ·..ri<" I' ' lIl,,,, ,,,,l..lit,,,, tlwl '~HlIl'ri .. · tI..· t"t,,1 p"tit '1I1 p,,"''''litlI"'..II.olit ,,,·n· .. I. I.,s. O,,s. ""tl ll. 7.~ u"i". n"I" ,," in·~· m" i"!t Ihat . .. ".l.i"l: i' ..·n·.... .. •.J, ·a r", ,,~· I ~' in.llId io", "... 111.", .~"t"· i. .... 10.. ~ ..1 in 1" 'P'd k' ,Ii..·"..·.
'1Il"""
,,,II,,,,,,,,,·
-t '"
"6
C HAPTt ~
13
hu t dn nut M Il Okt, ; ami t11( )'i.t' who Iw itlll' r 11iI\'(' lu-pat k- di.....·; l.w no r slIlokt" 111(" rd ati \"t' si".l.' and shape o f tilt' distrihulioll l"urvt' of each suhlx )j>ulatiou deterumn- tln- fn 'C lllt·n<.'y distriIJIIlio n for the en tire populat ion. If. 0 11 tilt" (ltllt'r hand. tilt' 1II( ·;L~lI rah l(· l'hamdNhtie is couuuuous. such as il~l'. wt·i ~h t . o r d(·~n"t· of n-nal funct ion . it Illay 1M:' possihle In find a funct jonal n-latlouship with ( JIl ( ' o r more p ha ml
n It. 13- 11.
TI,t' " '1...1 d . ·;
' porin. (·. ,flu id i lt..•• \1tI'Ws i ll ,hO'd p0'l ">rti"n I" ('W;otilli," ' dt-1ir-oUK't' in ;0 ItJUltp of 19 ptlil'n ls .. i th '....,.i"K.1o'W'..-s of .. .....1 (IIIK1io". I O n frolll tI..· "f "" n I>..L.". It.. Vr>"<', T ,8.. Ilioliln \ . ~ l.. ;0, ..1
150
•
.Lat.
•
•
T..m MIIMI. F..: 1><......" . lju.,t"....,1 (..r('('fluitliu.., ill I"' lirf," .. i lll hnpai .... 1n ·na! flllK1i,,'" Eum, J,eli". 11.... n"...u1., » .597..60'). 1w-.6.1
• •
•
•
•• ••
o
•
r
o
50
100
150
CreatinineClearance (mUmin)
•
Weight
•
Age
•
Renal Function
Oral Bioavailability
Volume of Distribution
"'x. 13-1 2. Sdll·m;olit.· n 'P"'""""',I;olit", o f
n,..
.il~'
"f
"~-i""t . 4/.
Renal Clearance
Hepatic Clearance
':ariahilit~, ill \';I.rio "l\ p....n na...J.in.1 it.· l'a ".ttll·h·". .., Ihi" " ''''1>11l.otio" , h h.I>I.... i'l n ·Ltt•..! to the .101t..... of ....riahih ty in til,' p;or-./I.. -n-r. nil' ("" rtl"" of ti ll' tal LtI,,·lt..1 n r ... rut! f"'K1 ;OIl " ,11,'(1 tiM" fnM.ik''' < of II.... lobI •...n..h; (,~' a<"ln " n t...1 fn r l~' ,·... t, o f tI · f...1"n.
CHAPIE P 13
217
o ra l hioa\"ailah ilily, volunu- of di stri bution. renal d c'a r.lIJt't', an d Ilt'p'll ie ck-aram-e. Tlu- siZt, of l'ildl lahlt'l is it measure uf \"ariilhilil)' o f l hal parumeter within tln- p auent populalio ll. Fur Ihh t1 n1~, 0 1',11 hioa \'aibhi hl)' is tln- II'il\1 a ml lll'pa lil' d t'ilfillll 't' is tln- lIlusl \"ari" "I,,. Slah 'l: l d ilTt' n 'lItly, ,gn'a tl's t l't lllfitll' lIt't, exrsts in ,lssi,gnilll?: Iht" populunou vakn- of oral laoil\"ait lhility In Iltt' IMlit'nl ; I" ,lst t'tl1lfidt 'lJ('t,t,dsts in a."si~ l i ll~ lilt' populattou \"alut, lIf1wjl al k d t'a filll('t' 10 IIIl' patie-n t . \I o n 'o n ' r. as l ilt' pOplllaliull slIlm-' fo r Ilt'p'l tie d l'al'd lll't' is much ,gn'at N than Ihat IIII' n-nal d c'MiUlI't' , \"aria b i lil~' in IOla l d t'a r.UlI't' wit hin li lt' popula tio ll h also hil-(h . ~ol llllt 's!lt'{:!t'dly , wd~h l at'l'tl,m ts for mo s t of ti lt' \"a riahilil)" in volunn- o f di sl rihulio n and fur SC llll(' o f tIl(' \"ariilhil i l~' in Ill'pill k ch-u nmce. A,gl', St' pam h'l:l fr om its inlhll'Ilt't' 011 Ilo d y SH'i~ILt , at't 'tlllllt\ for sonu- of l ilt' m rlabi lil)' in lJt"palic d t>a rdllt:t' a nti . 10 a II'sSt' r exn-nt, in vnluuu of dislri h ulioll . Ht' nal fllll11ioll alsll ac counts for almost all tlu- vuriahilitv in n' na l d l'a r.lllt'l', Surprisill~I~'I'H:rh"ps, n -ual fUIlt1iull lu-lps to ex plain SClllll' of t he s.uia hilit)· in Ilt'patit' d t'a l',lIIt't' alltl Hllu lIl" of dis lri llll tiHn, hu l tim !?: d h l rilm tio n a nd md"I Mllislll eau Ill' aln-n-d iu palit'lIls wil h renal flllletinll Impaimu-ut (St"t' C ha p . 16 ), Xom- o f tln- \.Irla hilily ill oral hio;wailahi lily is ;11't't1l1ll1c'l1 for h ut. a.s IIlt' ntio llt"tl. il is sma ll a nd il('t't'p la hlc' . Fil\;l lly, tht, ;Ila hility tn a('t'tlllllt for most of til(' \1lria hility ill IIt'palk- cl.. urun ce "hou ld Ill' 1U11111, ' l lIl" (If lilt, dlafilt·It'risl it~ illd udt't) t'tlliltl atlt 11l1atd .... account for Ih,' inll,wnl" of ~t 'ndil's , d is.: ast' , am i 011\1'1' d m;.:s tin this (lOlfillllt'!I' r. Ma rke rs of ~l'lIt'l il' control o f ti m ;.: IIlt'lahnl is111 !taw Ill'l'lJ t1I'\l'IOIIl'c1 llml he-lp 10 I·,' plain much u f tilt' inllt'rltt'l:l inlt 'rl nl lisiduill t1i1Tl'rl'Il('('s in hC'piltit' d t'a ralil't ' of ce-rtai n d ",~ (C h;lp, 1,1), Ft··w,1l 0\ \l'\ ·..-r, a rt' I'lllplnyt'tl d init·aUS'. HI 't 'l m i ll ~ III till' ill" lili"I'MI IMli" III, t't lm'(1 i n~ tilt' l'H lp'llal io n plllln uat'u khwl il'S for tlupal it'lll 's s\"('iJ.:hl. a1-(t', ami n-nul Iuru-t iou should ~n' w aso llilhlt' imlivnlual t-slima ks of F. V, a lltl Cl ' H hILt Htt lt· l'tm (jtlt'llt't' in tilt' 1'~ lim alt· of CI. II andlu-ucc totul d t'ar.uK't·, :h tilt' IOlti'l F/\ ' " l rc lll ~ly illllu t'llt" S ti lt' )waJ.: pl.lsma t"l lllt"t'lItmlio!l aft t'( a si ll~11' dose. n-asonabkt't III fid" 1ll't' cnn Ill' I" Ilt't iI'll in I'sl imali llJ' tln- Il;llit"llf S 10.1( linJ' tlost,. if requt n -d. II UWI'H' r, sillt't, tilt' filtio f /Cl. 1"l llllmls l ilt, aH'fil!-(t· plat eau coucentranon. les s t1mfitlt' nl 't' t' lll Ill' l's!'N't ·It'l1 ill I'sti ma l illl-( tln- !l;llic'llfs mainlt'!I,lIll 't' tlOSt' n'f!Llil'l' uw nts . If tilt' t1lt'm p,,'u tit' indt 's o f IIII' t1 nlg: is sllllieicollily l lam'\\", tllt' n ' lIIay hc.' it ( ';l'\t' fo r lII()n i l (l rlll ~ tilt' p lil\ lIl<1 t'tlllt't 'lll lOlliOIl 10 aid in adjll"ti n~ tIll' lIlainlt'll'IllI't' t!osillR fillt' Ih mu!!h fet'(lhat-J.: a.s t1t'sl.'lillt' d in C hap . I "i (Co l1('('111ration :\1o nilori IJ~). ~ o llt'l llt' lt'ss, lilt' ('sli ma tl' of lIIainl('II,lIJt't' ,Insc' 1"'''' '11 l UI III,,' inf"lflllalillll p m";,,I"'l:1 iu FiJ.:. 13- 12 ~ III II I ld Ill, lll,ltl' r tllan u"in,glI,t, 1Il1"1Il l);m urll'lt' r \"a llll'.\ for IILl' wllolt, IlllpulalioTl . C lt'lIrI,.. if til(' d m ~ had just Ill"t'li l'xI'n ' h'( l lult'h all.Il:C'f1. 1111' pmhabilily of I ll'i ll~ ah lc' tn " sfi malt' tilt' t'tlm't't d us.a!-,w " 1-rimt 'll for 11ll' patit'lll \n lHltl han ' Ill'" u IIIm ·h h i~l lt , r. TI ll' appm,;\(' h pn'St'IIIt'f1 a lM,q' fo r pn '( l it'l i ,, ~ an im lh i d ua l's do..aJ.:I' n 'gi lllC'lI Ill,fort, aollllini'kriul! 11ll' t1nl~ is ha ",'(1 011 lilt' .t\s llln ptio n th"l lilt l.. in!l'rimli\i l illal \1Iriahilil)' in phan ual"l M I~l la m i l~ ,'sisls. T ilis is not a lwuYl; SC I. Su mt'l illll's, 1II11li1 of Ihl' s'ari ahility in 1'1 " S('H IIl'\(' is dILl' 10 d i ITI 'n 'n l't '~ ill pharll1at'tM I~l l;uni( ~, A lt lJllu~h J.:lll lS\ill~ tilt' llll'an phannat'tlkilldit' pamlllt · It '~ of till' dnl l-( 1I1;ly 1ll'lplo ,'s plain Ihl' ti lllt' t"l llll""l' in n ";I'M msc', tlll
211
CHAPTER 13
STUDY PROBLEMS (An swers 10
Study Problems or e in Append ix II.)
I . a. List tim ..' major SU lI rt't·S o f \-ariah ility i ll rt·spem....• 10 Il{'(' inte-rvals] from til(' popula tioll value-s uf F, n.S2, ant! " , 10,3 L. Hril'f1y di scu ss how tlJis (''Uuld ari sl'. .5. Lithiu m. IISt'(1 ill till' tn ';lt lllt'll l of p at ients wi th manic depn-scion. is Ul.lmillisteR"t1 d ln lllie;llIy. "I1Lt' IIw ra peul i<.' \\; m low of thi s d nl~ is na rr ow (0 .4 10 IAmillit'(luinlle ntsl Ll. its fi' is l , its alld t1usa~t' n - quirerm-nts \1 11)' \\;dt·ly a lll(Jll~ patients. a. \ \ '!lal h a major l-:IIISt' o f tllh \'ari;lbi l i t~' ill dll-.a~( '? II, \\ 'hat characterisne or a l" ltil' llt should IIt'!p to tai lor lus o r ln-r dOS;I~t, rt''1uin'lIl('llt ? Ii III a J.:WIlJl of I.t';llth y sllhjl"t.1s, ti lt' a\'t' r-.t~l' p hilnllill11kim 'til' p arameters o f Iht' jl-ad r('IIl'!,¢ l' hl (ll'kill~ a~(' lI t alpn'llolnl. whit' '' is t'!illlinak d allllos t t'xcillsi\'d y hy ht'!" il k lIlt'taboli slll , W('J'(' Iound tn hI' vohune o f dis tri hutjou, :2.10 L: clearance, 1,f16 11111in ; am i half-life . 2,.5 h r. AfiN Lv. admiuistratkm, vnhu-s uf ti lt'S(' parall wlt 'rs t1ilit' n , llittl t' wi thiu Ihis V;Wllp ; ) '(' 1. w llt'll the- tl n lV; was i ll~t'sh't1 o ra lly. IMltt. pl'a k pl asm a concentnuton am l /\l'e varied over a fi vefold rd ll~l' , S lIggl 'st why \'a oabj lit~, in the observed pt LsllIa ccne-ntrunon-tt nw l'1l1',"t' is much ~n'alt'r aflt'r elml than aftt'r i.v. adtni nistraI iOIJ. 7, T hl ' rull owin~ data (T " hll' 13-3) wert- obt ail\{'tl ill a siudy o f the pIHlm ml'()kim 'ti<.· vl,riahility of a d nl~ tl ilit is pn,IOInillantly t' :u'rt,lt't lll nd l llll ~I'tI , fi' = O,W) , TIlt" tl nl~ was illfuS('t1 int mn 'llo11sly ill fin ' slIbj{"t.1s at a consta nt m it' (If 2tl lllgtlir for 41'1 1.1'. T Ilt' fraction unbcuud "-:L~ fonm l 101M' im!t,!)(,lItltolll o f t1 nl~ coucentrattou hil i di d n u)' m llell\~ tilt' subject s. f.It•• 13-3.
"'' ' ' ,
511:.'Odywle ploYTlO co-c e-e once Img!L] PO$I,n/v$1QIl HoK~,1e lh'l F'OCIIQll
""bound
'0
3 30
4 15
5 13
14 4
50
47
00
81
0 1
015
000
01 0
001
1 15
1
a, t\ naly,.l' tln- dala to id t' ntify tlu- II1m t l\ndl l.t" least vanabh- (use till' rml/!.I'IIIl~ '(/11 as YUill' illllt'l{ flf \~l ri ahi li ty ) o f tilt' follo\\; I1 ~ p;trlillwh'n: C lt'ara nl,(' hll.... -d 011 lInlMllllld d nl~ (C 1.,, ), fracti on u nhu und in plasma (fr d . aut l fr.wtioll liIlIMIIIIlt! ill liss\lt· (fr 1r )' US(, a " nl' of 39 L. b , D iM'uss b';t,lIy tilt· 11lt' r.II)('lllk' illlp !im tiolls of liteS(' tlata \\; th rt'~artl to tht' rai l' of ;lllaillllll'nt ;Ultl lllainh 'Il;Ull,(' ofa "thl'm lx'utic" l'()IIl"L'nlmtioli ill ti lt' \-:t rio lls sUhjl"t.1s,
OWTE ~
13
2 ••
!'t. 111t:' u,'i% n mfldl"lwt" Inn-real o f l'!"ara,I(." u f a 1. 1 0l ~ within a patient p upuh&lioll is I..'> In ; .5 [A ll, a I.lifTt"n 'l1n:, of fin_'fold. Other pharmac:ukindic 1lly \\ilh tilt" d rug, alKl lKlt tiM;' md.,h.. n litt"'\. 1>i'>("\I.... lilt" p lt,"ntlal illlp
"
1~
GE NETICS
OBJECTIVES The reoder will be able 10: 1 Give e...omples of mherifed IIQriobilily in pharmacokinetics and phormocodynomics. 2 . Define the terms; phOfmocogeoetiO. genorype, phenotype, genetiC po/ymofphism. idiosyncrasy. allele, homoZ'f9OU$. and hetefOzygClUs 3 DemooslfOIe how pccccrco studiesand sludie$ in twins can be used 10 ind;.cole the eoseoce 01 generic po/ymofphism . 4 Stote undef wha l circumstonce$ pher'lOlype ~lus is 01 therapeutic votoe. 5. Describe alleasl ""-'0 ways. orhet Ihon twin studies. in wnich generIC po/ymofphi!>lTl con be demon!>lfo!OO and lisl I'M:> examples01 each.
luhe ritance accounts for
;l
la~('
part or both lilt' ~ t ri kill~ ,lilt! slIhtll" t1ifTt"n 'Jl('t's alllOll ~
Individuals. illcllldill ~ mu ch o r tlu- vartat inu ill n 'SIXJIlM' to uu admtutsten-d dm~. 1'11(1'" 1!I(/ l'f1/.:I'lIe tlcs is tl u- study of Ilt'rt'tlitary variatums ill d m ~ rt·S p OIlM' . " (·fort, p n K"t't 'tlill l-'( til t1msidt 'r spl"'l'ific csa mpk-s, sonu- dt ·finitillllS an ' im po rtant 10 all 1I1l(1(' rsl alid ill ~ o f tlU' .~ ll h~ '(1.
111t" h'LSic hiol(~('1l111 Ilil nflw rt'tlit)' is till' ~(' IlI' . (;nwl Ylw is th e fundamen tul asso muent of ~l'Ilt'S of all imli\i dual, tlu- bhu-print, wlnh- , l/wll OfYIH' is till' ou tward (:lmral1t'rislit' l'xprl-'ssioll of 1111 ind i\id llal. 111(' modi' o f iulu-ri tance is r-ithcr lIlm ll ~t 'n k (I I' poIY~t'"it· dt111'lldi ll ~ UII whetln-r it is trallSlll itl t"l! by a ~PJl(' al a si n~lt· lot'lls or hy ~t' I WS at umltipkIud on tilt" chnIlIlUSOlllt·s. T ah lt·s )+-.I ami 14- 2 list ~t' l \('t ie o uuhttons th ai alTt"l1 rlupt.,tnTl,tl."Ilkillt'l k s and phannal1MI)1l'Uuit'S of some d n l,L,'S. All o f t!.t'st' condmons arl-OtransllIilh"lllll(JIl( ~(,ll il·ally. !Iolall)' an' t·xp l1....st"l1 as POl)ll1l1'llhisllls. utl lt'fS 'lS ran.' pln-uotypes. C ern-tic polymu rph ism dd ilws Il\ll1llJgt' nie traits tllat exist ill tlu- nor mal pup"latiull ill at It'ast two pla-notypes. lw itllt'r uf which is m il.' (It'SS tliau 1% ). !Io 1 ()llI ~t' n i mlly t1mtl1.lllt"l1 t"llnd itiulls ure uf'tt·n dt'h"l11"l1 as a drnmatk- anti. nhnormal t l m~ n ·slxlTlst·, that is, tI elmg Idlw'Yll cm...y, l111'y 111<1) ' also 1M.' t1eh "l1t"ll ill population stullies hy a POIYlllfMlal fn'( llit' lll) ' t1ist rihllliull o f til(' l'hamd t'ristit' ur SOIlIt' 1IIt'.lSIII't· uf it . 1'()ly~t'n it'lIl1y controlk-d \'ariatinm W\"c rist· to a ununod al fn"
221
GEr-..fTIC5
CHAPTH 14
Tabl . 14- 1. Som. G.n.tlcally D.t.rnllnat.cI Yarlatlonlln Pharmacokln. tJu
,
" . !.;
«, ..... A.
",
" ....../
..~.,
' ..
,. . . f<
Pot)< .......vue Il""~ '"'cr"
" . •'",'-1: v ~ ;>()')O'
'II '.fl.-', i
,',<
l ,
5-1 0% Co<JCo,'O~, 3 8\ Bkx"
CYfI'2D6
,"'7\0'. ",
OQ%
O~IO:S
I%A,o~
Enco'nid.. lIecoonid& bohoIoI. rimoIoI. co de!ne. O'I()I1fi~ine, l'Illlklp'oIoI, de.xtr0'
-
melhatpCll'\, spcY'
reine. and perne,o.~
P'oor and exlen<
-"
s,~hyd,o""'"
ohon oI5-m& P'oor and exlell"
>w """""" !lOll 01 &mtorcoploput"'.e Slow ond loll
,sonlOZ,d 01 """"'''''
Poor '""""'"1OC re ,~ "'0-, CYP2CI18?1
,hO.'
3-5\ CO'.«l\,o<\S IO%O-'IOI~
.oc-eosed Y'
-]'::"0"
~"p.d "'''''';-',10'0<1 ""0, 1"0'" 'g' .~. U
~
14% CQl>CO~Kln~
IkM "'""!tlyIa,oO<'
..~.~ ..", I"1 ,,,
00% Ccocovoos
$-e", " ,.' ,.Io'QI~ ma .. ~'CW 10'"
1o-zos Or,enlO's and Es.,'"'O!o
'i
s..,...,ol cb-oe-or ~,mmtcQn' rTIQ(l
d'lOIdoo< 1 ..
2500
, ...1.14-2.
o.-tIc.11yhhrM. . . . . V.... A
'. Warton"
.tI_.
s.._
re\lS'
eece
,
'.
L"'J(.' .......'
"C·W.
'
'"
~t's1 ~lc 'X '" 10 O'
, oagJ!a"
"""'.1"
I..........
if '
l'
,'.
""""d~ or enzyme ,n
I;'OJ!"~.
" "")1'..'>1
'2
wG'bin
Ialge ped-q-ees
~<,
,..,
liver witl in~ol"nlty
_I
b vikJmln K
~(JVIsm Of
d,veind\ICed he-
rrdyric onem<
~moI i l , '" -e soc-so '0 C"," ' " 'I
G<"""""
phole dehyd'O'
...... 1G6PO
'1''''J'
Awo "'1"\0 '~ 100
"'11100<'
c'teoed
,n
NO'ld occv', ,n hogh
f'eQlIf'rIC',i
.vh
Votiely of d"-'9'. e,9" ocelonillde, pimo~,~ lOin, ond chbom-
.........
d,s' "Cl
"-'VlOl,O"S Gb<~
AonOt""l'
Un~r'IOWI'I
'eo-
App' o,, "Xl ~V 5"
~old>
USA popo!a"O"
'POn<,/> c) ... ~Txuk:J' C'''\"
""e'c
oVolignant h.,.
-~
>~O'j
""" ':h,CI
Ueccoeo l<>
g;.j ',
t'
C0 2 . binding
..-
ApprO> rna~y 1 ,n a~I">e" l~OO'_ls
I 5,000
VOfious aneslhetia,
""""'' hal> .....
GENfTIC5
CH.\PTH 14
~ I ll rl' thuu Ullt· inlll' ritah lt· dlilnleft'ri slic llIay lit, pn'st'lIt 011 till' same pai r or allel es . For 1·,\1Ullpll', thl' ~,· IIt'S roT h10UII l)llt'S A. n. am i 0 an ' in tilt' "<11Il1' pos ition 0 11 ulh-k-s.
INHUITID VARIATION IN PHARMACOKINETICS E\1lll1pl" s or illht'ri h"(1 \"aria bilit)- ill p h u n ml(·o kilwt il-s !Ia \"{. hl"('11 a lmost l'xdusi\'t,ly n -sl n d ''ll 10 d m~ 1I1('la"o lislll _ Henal "xc rl'ti nn or dOl~S diM'S 1I0t apllt' ar til show ~l'lIt'tk pul)l norphism ; tilt' renal rh-arance- for :my dOl Jt h·lltls 10 1)(' similar in a~l" ami \\1.' i ~h t matched. Iwallhy slIhjl'ds _As a (:umll:uy , t1nt~S Ihat an- pn..:lo m illan lly t'\t·n·tt"(1 uuchauged n-ml to vhow 1Il1l(:h It·ss illlt'rim ih idllal \~I riahility ill d ispos ition kineti cs than cxtellsi\'t'!)IIll'la IMlli:t.t"(1 ()I 1" S. nl" d, ;:n't' 10 wh ich varia bi lity ill t l nt~ uhso rp tiull und di strihlltioll is under ~t ·1 11 ·tit- contr ol is P(Mlrly d(,hllt"(1. Ct ·rtaillly, there an' st'\\·r.al varian ts or " I-alid I:lyt"(lpmlt'ill t- xp n-sv-d POI)lIlOl"]lhi l'1i7.t·rs, rollt)\\ill.l: unfilial dust's or til.. art'h('l)llic tlm JtS _ A Tim ' p lwllol)]lt' is st'('11 with SIK."li llylt'hnlillt' , T )llit'a ll)", mlls<'I(, pilmlpis w t ' urs of]" within minutes or d ist1 111 ti ll lli ll ~ thi s lIt'Uft)IIl11st-lIlar hlucki ll ~ al:t'lIl, Ilt,(~.lll st· il is mpidl)" lIyo:.lmlyt.t't1 to inat1:in' products. cholu«- lind 1Il011( ISIlt"l'inyldl(llil1t·, I,y p l:l~ lIla and Iwpalit' pst'lIdo,:holillt'sh'TOlst'S_ In an occasional pam -ut , howt'n 'r . Ilt'u n llllllst'u lar h ltx-katll' 111;1)" 1a.\1 sevr -ml hou rs arh'r s l opp i ll ~ tilt' tnfuslou. 11t't'illlst· hydmlY"iis is lIludl sl()\\"t'r than IIsua l. 11lt, rt':('.OIl is lilt' ('\islt 'Ut"l' or an ill)]lit'ill t' IIZ)"lI1t' rather Ih.1Il a lower concentration or II\(' typical t'holim ·sh ·rol-st·; lilt' at)Vit'il! cholin('slt 'TOl"" h'l\ oulv 1/ )(10111 o r tilt ' usual affinilY for succiuvk-holuu-, am i il 11t·1..I\,t,\ d ilTt'n'nthrWTII lin ' l)lllt'ili dl(l!ill('sh'rol-st· tn va rious t:lIZ)l l1t' illh iililur,;_ ~lallY aberra nt rUTlIlS or th~· ('IIZ\"Ill" ure II flW know n 10 e xist, t'il(,h dt'lt·flJlillt..:! hy a di fTt'f( 'nl ~t'IIt· ,
Oxldatiotl \l osl slIIall lipnphilit, d n l~s aft· sU" jl"(1: tu u\io:latitm by tl.t· t)1od lrt>JI\(, !'-4.')O mixe-d [nne -
ttou n\idatinll S)"Slt' IlI, primarily 10t'ilh '(l wi thin the li\"t'r hul alst) round r-lsewlu-n- sud l a _<; til(' ~1I 1 wall. T his SUjlt'Tram il)", whid l t11lllp risc.'S lIlallY t·IlZ)-lllt' S. is lIPS (Tuh lt, 1-1- 1). It is a rt"('('\Sin ' Int il. eoillst'(l by a t1 t'rt 'C.1: 011 a S ill~lt, d lrt)JIlOstlll\(·. Ihal a fTt't.1:s a IlOlrti ("lIlar H\ ida lin' 1·1IZ)'lIIt·, dt'brist"l uiut· h)l lm \ )t l....' (C n h ,2D6). Sillt't· Ih is di st.."l )\"t'I')-, a wholl' hos t or t1nl~s, ind uo:lilll-:: TIlt'l opmlol ( Fi~_ 14--1) ami tht' untiarrh) 1:h mit· d n ll-:: t'IK.'llinitlt· (T:lhlt, 14-1 ) han ' h''('n rflum l to ht' suhs i rolll's rOT this t'IlZHIlt', ~ bllY dfll~s an ' o:l.\ itliu'(! \\ith \\i ddy difT('rill~ (·llidl·ndl·; hy Iht' d ifTt' Tt'ut ronm o r t) 1o(-h n llll(' 1'-4,')(111.011 (·,ist in atidi tiull ttl dt' hri stWlnillt· h) t l n>~tl'i(" n it' d('aT;lIIt"l' \lIlu('S
223
GlNETlCS
CHAPTEIl 1.1
a.ssodah"tl \\i tl. tilt" oxidatioll of certain dmgs n lSt~n~att', imliedlillg that thl'Y an- substrales for till' SOUllt' l'1I0 11\(' (Fig. 14---2 ). There is also co nsiderable overlap in tilt" strucm rul s!)("l'ifid ty u f SOIllt" of tilt'S(' ( ·II ":y IlWS . such tha t a dmg may 1)(· a substrate for mort ' tha n ( lilt> of tln-m. E\itlt 'Il{1.' famring g('nd i(' coutrol of IImny of tilt'S(, p r'Ol't'SSt-'S is gaill("ll from studh-s \\i t1l twi ns. Fig. I W Illustrates such an ilJ\'('Sligalioli with tilt" antid t'prt'Ssant dr ug nortripl ~'lillt" Variahility in the plateau pl;l~lIIa Ilort riptylim. concentration after oral ad miui stmtioll ilUlllllg Identfcul twi us is mill'll k-ss than among fraternal twins or, ind t't"l l. alllong auy r..lI1domly St,lt·eh '(l. agl'-maldl('tl gnltlp. Similar data ('xist for otllt'r d m gs. AI· tbough III,' ,·\itl,' l!('(· pn'Sl.'nh'tl in Figs. 14- 1 alltl 14-3 an ' striking. anal~""ii s !lll"''ti sol,·ly on 1111' 1II1("hangt'(l dm g ill phlsma IlIay hI' misleading. Consider, for t'X
Acetylotion Imlh i dllals \'a r:' \\i dt'ly in their t'limination killt'lil's of tiK' antitube-rcular t1 n lg iso niil7j d . TIlt' himodalil y uf lilt' frt·ljlwllt·y distribution his!ogmm of the s- hr plasma ifotllliazitl cont't'lltratioll follo\\i ng a s i n.~ lt, oral do'i(' (F ig. 14-t) W
600
"·ill:. I ,J- I. 1>(",. ",.. 1I1t'l"I'" .~ >1 " ""'f'n t rnIMIt'~ af" 'r .. 'i nfd.· tI"oJ ,...... " f 21 _1 "' Km''f orml..! l;&rtr..t.· ,...... ilION'" l,jlQlt'r ill I".,r (0) II,all in , k .,.uw (. J I,~'.l n lll~·LI"n " f ''' ·''';''.I"i'It·. H ,.." llN'1"I'",It>l i' .. .In'K of hi~1 Ilt-p.otk d.·ar...k tI lirr.·"~ K~· I...·· m...·" 1"." ......1 '·~l ..'''r..· nN'1 ..I. ~i h·'" i . '·.p""""..l in , I..• Lal'):t· .lJrr'·"·IK~· in .. r.tI I.i ",.iJaloilil~· . •1,..· I" .lJrr.·...·,...~..in fi"'I.f"l" IN,...' it· , n..·,,·rht...I Ii'k'S i'kl..:alt· lI ...• " .....L.n! .w,.;.,IMN' (I "'WI. - 3.7 ", .'1 ), i tk.. lnt\\~1 r"""I .~",,,nl. \l.S.. Sit.". J II .. Fn....'.....·. s .. ",, "' '''y. L.t-:.. T,.. ·ln. GT .. " 'k l W... 1... II.F.: ("MLI "~ p1N·'. ~l"-"'- ", ..jt ... d.'1,·nnilla nl "f .,..." '1," IIt~ IIN'fal• .ti,,,, M! ""'1""-..,..... 1t' 1',;" ,...1loy I" 'r",i..I"" nr n... S · EUI:I",1t1 l"u m,.] uf \l ,.. liti,It·. Jt!7: IM't- IYilI. !lj'):!,)
z:
-='" ;";; 400 C c
~
u
c 0 u
~
5B ~
'"
200
.
~
E ~
~
.
,
0 0
6
12 Hours
18
24
G{NETICS
CHAl'lU 14
houiMjd is prilll ari l~' i!('t,t,.lalt'tl in tilt" liH'r to S -aet1ylisu niMjd , a p n 't'u ('\()r o f a ln-palolo\i(· l'u lIlIX)\lIul; tlifft'I"\'ll l,('s ill III(' 1·limina lio n kim-tics o f lscmiazic] rdlt'l1 po lymorph ism lIf a particular ~ -a('t'tylt rallsft,r:.L'i(' NAT2 , a e:.10';ulic t'IIZ)1I1t'. As sho'l1I ill Ta blt' 14......1. l a ~t ' gt ,1lt,tim ll, · l'tJlllrIJllt'tl t'lhnil' d ifTt' '''IK't.'S t'xist in tilt' di sl rihll liull of ill't'tylalur sta t us. Moth Ca"('l.L~i ilIlS a nd blacks !la\"(' ap p n n illmtdy t'(l" al nurulx-rs (If slow a nd fast an·tyla toN, hut in (Irtr-ntal a mi Eskimo populations tilt' Ilt' n.'t'nt of slow ,l('('tylator; is much small" r. S low 11l1,t,latoN an' ~t'll l't i('all~' !lu lIl0 I)"K0 US 'lith a I't"t.'('ssin' allele pai r, ami 1)(·cauw lll't't, latoTsta t us is umll'T mollt ~t'lli c co nt rol, it is IXlssiblt' 10 calcula te the fl't't lllt'IJ(')' of llt'tl'TU0 Wm s a mi ho mo0~ulI s filst iK't,t" lators From KI'IIl' Frequencies. The results of 0 .350 (21 /(/ ) o r 3.'i.9'l a lll i o.oss CIT s.s« . rt'sl)('(1i,'t'iy.
,,2
(f,z>
SUBSTRATES:
S-Mephenytoin Diazepam Tolbutamide
s-wartann
Niled ipine Erythromycin Cyclosporine
Phenytoin
3A-3-5
2C·Meph
2E-1
Fu rafylline
Sufphapbenazole INHIBITORS:
Desipramine Dextromelhorphan Debnscquine Caffeine Chlorzoxazone Theophylline Ethanol
xeteconazoie
Quinidine
F i,e:. 1.... 2 . ( :rul'hic: nl' n... ·" IA i.." " f tl lf' ,Mf'·Il·"t ("01" " f l~t"d' "," If ·. I'-&.'il ) k i n' Io'S ) in IUIlU.III' with lIiff,·n·" t 11f,1 ,"'",. ,,,.·.lapp;",, . "I" tl'll'" '''If1 IIn..I,Kt ' I"'fifio.itj,-" 11,,illf!ic"Io' '; "10:10, "" -,,,J,fJil,- p"tl,.......~.... It,,,.. n....·ll l ati..•.. ,I...l r..h.. " n' 1i.1o'f1"ho..., f"r .....·h " "zy"'''. AI.. , Ih" 'fl " ",·Lith.·!)·...I....tj,., i" l,ihit"n " f th.· '-"1:)1""'" ( Fn Ull ".·ll"f"'1'. 0. "",I Ih ,..;,,,..,.. 1) .Il .: 1101.. of .. ,,' 1n"''''' '1 ,t,,1( 1"" in ,I..· ph"rmo.c.. kinrt ICS " f .Im",: Cun ' ...I.·r.d.",,. ,..tI. n"'I"'f1 In "",,,u1 " 10·1•. l'-&.'it) ''1I~'' ''· . .11,,11'""'" c1n,lt"'. I" 11",,,11... 01< "f F.~pt'ri ,,,,·nl..l l"h.or_ l1l;.m lo'l{' . \ ',J. IlU . 11,,,n n.... oI
Ct-WTE ~
ce-ercs
14
Identical Twins
80
225
Fraternal Twins
80
~
5
~~60 e s t: 0
-
~
.g
Z
60
~
c
E
~
!!
""
40
~ e, u
c
~
~
0
20
~u
~
0
40
Irn m~~1 ~
20 0
~
~ ~~~~
I>.""...
HI(. I ~J. 11... mud. "".,II,·r ,,,It''l'.ur \an.."i l'I~· in "1..1.·..,, pt...,,,,.. nIlK" nlntl~ II' or 'K .rt ri pl~~1r"· ·n (Ill iol.·"ti.".,1 I" i'" ,I,.." I"·",..·,, l II I (mh·o ,.,I I"i'" "" 111·;01.... !I,,,I !o:' ·tl"'"" I>I .~ . It "",j" t ... It· i" .1I ....n l'''~Ii , ,,·l'hltt . ,,, l .,,1'1...... F",""I,· I, L,tl " .I" r); n...I,· ( 1l~1 ' 1 ,..Iorl. l t 'n"" ,. .......,.. 10·... ",. It , I'nn ·· t:,"ltJl' . ILo\.. It'K I Sjo'Io(\·" '. F., " ·.lIh.'I.'I.· I'L.,,,,., 10·",1, II( ' l 'rt nI'I~ I ,, " · III ""in" I"A,,,,. ,,..· ..( 10:" ''''';'' (...1"" ..,..I t1now: 1 1"·n.I'~· ' Il r . \1...1
J. ' 7f>.1 ~7h"'.
1'lh'J )
. l lt. 1-'-4.
25
tl
s ...
20
'"
hi'III "W ,1."' nl" 'I;'... •J tI,,· I>- I,r 1........ in .....1 .,,1'J"'1' ..flrr
fII( 1..w: i
~ ~It. (nwn • • ~t.t...
f" ~lt.""".. lII ll nll'.'1. -
7.3 11 \11. ( Ko..l lt (n wn E' .lm . Il.o\ P.. \I ..... ~ ":..0\ . ;and \I (..:" -\.. \' ..0\ : (:'-"'1..- n ..ln" "I iJl ",i.uitI nll"l..t"oI;,.m in n.... ' fl r , \1...1. J. 2 ......')....&.,1. 19fIl11
:5 ~
n
pL&-..... ,,,,,,,,,,,,,1 "
15
" 10 ;;; E
D
~
z
5 0
o
4
8
12
Plasma Isoniazid Concentration (mgIL)
-,
1"-5' .oaT'>1,.-l.TQr5
.OW
Soo..I'h Ind-on~ C~~
Bloc', f .~
-C
....
~-
....'o::Jdn»
.J' .
.-
, ..
"~ , <
,
356 350
54 55
386
08
43 8
45 7
45 3
42 7
408
282
,~
<.: • ":?--J'
,
22.
G£NE T1CS
CHAPTER 14
Isoniazi d is au ex eept ton. In must (~.l"'-·S tilt" fn "fjl ll" ll l'y of I M:t:ll rn"lIl't " of an alll'll' is linked ll~ ~t ·Jl(lt ·r. Also . several sul'l-:rtllips within till' ~t'l lt"ml populutlon a n ' uflt'n o f a ",rivt'll (·th llidty. TIleS(' dTt'i.:ls ma ke il lIillit-lIlt 10 1~lkll l ak the ~t ' ll ol~l"l(' fn'(jlll"Il I'y . Hnwever, llot\\ilh stml(lil1 ~ tl1l'dillkultit's ill makill~ p n -d o;(' ('1' ,lsso l:ia h'l! with d t'\"a h 'll pLtsm;t conceut rations of hytlmlazim' a nd jHlIt'ain alll id t" Hapt d iu'('lyla llJl'S a lsH n 'lluin' higllt'r
wnh o l !Je f Iact nrs . suc h
AdGrtiollaI C1inkal C..lidefations Sl'\l'ml poinls nr-ed tn lit, llIatll' ill ad dilioll In t hllS{' matll' a ln 'ady. Fi rst , IIII' chnical implicat ion s of gl'lWtil' pol ylIlU'1)hislIl ill d l1.l~ 1llt'lal MllislII d l,)lt'ml nil whe-tlu-r al'li \ity lit'S \\i l h tilt' a fTedl'l! snhs l rdte o r tilt' IIlt'lal Mllile. RS Wt,lI ilS II.I'" importance of II.... palhwa y tn ovr-rall r-liruination. Fo r tlnags SII{·I. llS d l'h ri.Sl Ml nim'. al'lhily rt'sitll's p rt'l )mnim llltly wi l l. the dn l ~. ilm! elmununon is al mos l l'UIlIp!l'I""y via tin- a lft'{1t'l ! path w,ly, In slll' I. l'ilSI'S, unk-ss lilt' d lls{' is n-duced. 1I10n ' pronouncecl a m) sus num- d l,ffl'l1s lIlay IK"(:lIr ll ~l'I llt' r \\i l l. po te lli ially mu re frequent a dn 'rst' react ions in I'MMlr nwlaI MIIi".t' rs. A l~ lll i filsti n~ a nd illh'n'stin~ sit ua tiou is St"(' n wi th l"(M!l'i l1e . Part of its an algl'"sil' al'l i\i ty is due In morphn«(u nTIl'll From I'l'M !l'i!1(' hy tlt'b riSlM llIilJ(' hyl! RJ\) -h 'i(' (; \' 1'2 1)6). Al'n mlingly, suIJjt'l '1s tldi cieu t in dd lriSl Mluilll' hydmxyhl'il' lIlay d l' rin ' Il'ss ,lIlall-:l'sil' " {'Iwril fm m l'l'MIt'int, . TIl(' l'l'lIl\"l'rsioll of lilt' a nlilllllt'n'lI]a r tlm ~ tlapSl lllt' 10 :-':';lI '(,ty]lbpSlIIll' h y S -at'l"lyltmllsfl' m'i(' l'xhihils l-:t'lw lil- PO I~l l\0'1) lJi slll . 1I0w l"'-I' r, ilS ilt'('lyla tiull is a mino r pa tllway o f
GENETICS
CHAPIEI1 l A
221
cokinc-tics, ami rt '~ I)( II l\(" may Ill:' lI\isSl,'(1 unt il tilt· dm~ 1)('('()JIws \\idt'ly prescribed. wit h polt'lltially St'riUIIS (,( ll\St'C IIll'Il('t'S, Fortu nately, \\ith the.' illl'rc."L~ill~ amilah ilit), o f pun ' hu man t1mg-I1lt' laholi zill!-! t'1I0 111t·S, prodnccdustng hiol ('('hnolo!(\', prt'('linim l i " dtm S{'n.'(' I1~ art' hq~illllin ~ 10 1M.' I I.~t'(l l o e.,haradt>ril.l' lilt> 1'1l1.)1111'S primarily n 'spollSihll' for nwtahoJjsllI (If a d m g. If tlu- l"nzyll lt' invulved is one- known to d isp lay gt'l ll'tk POIPllUlVh islll, tilt' dmg ranl x- evaluated ill a pn-seb-cn-d ~n lll p o f suhjt'(1s \\i I1l Ihe t'1I7)111t' dl'fi l'il'III'y to ecunuuwhetlu-r St·rillllS pmhlt,tIIs migh l ari'\(, duri ng its sub'\('(!1Il'1I1 use .
INHERITED VARIATION IN PHARMACODYNAMICS :\ ~ p n"\'i l)Il ~ly 1I0!t'i.1. palit'n ls n ll'Y in Iht' dllSllgl' n-qutrcmcnts o f warfarin 11('('(lt'(l to pm(hll't, atlt" ILlalt' anli('(lagulant control. At IIImt, till' variation in d{)S:I~I' n-quln-meuts is fivefold , In sr-veralnn-mbe-rs of Sl, 1I11t" famil it's, however, lIIiL\.sin ' closes of wa rfa rin an' 11I,('11t'(l 10 ;(l'hit"\l' a 111t'r.lpt'ul k ft'SPOIIW. Figurt· 14-,5 Illustrates tln- Hudmgs ill h m familit,s. III ('{ lIl1JlLOII \\i lll rulu-r ~t' llt" t k traits. warfarin rt'~ ist a n('(' is not found ill all kindred. Anal)",is o f tilt' frt" lllt'Jl('y o f ti lt' n-sistancv in Sl,...e ral ~t' Ilt" r.lt i(Jn s i nd ic.~dh's that Iht, n 'sistmll't' is a domiuaut d laral"lt-ristk t r.ln~rnillt'd in a single gt·llt·, A normal phanmll"llkillt'lk pmfilt· o f warfarin in tilt' n -sb tant sllhjt'(1s points to a phanna('()(I)lla miC'illly !J;l....'(1 fesistall(,(·. A p rnba lll{· Illt'l.'!Mll islll is irwn.'ll<;('(1affinily or tilt, n ,('t'ptof for vitamin K. with which warfarin
Table 14-4. Potential Conseq uences of Generic Polymorphism Invotving Drug and Metabolite for Poor Metabolize,.-
'-
~ aled reponse, PQIllI"IliaI
lOxicity
..........
o
o
•
M
D M
I
C HAPTE ~
14
F I". I ~, H... hM1i"n "f 11.. , ,....'.,t" W" rn ll lln ll'" hin ild i.ih' Ian h "f ""lit~t;&,,,Ld>ihh' l fn ll n n I.. 4!'l I,r, "ft,,~ .." ur"! , " f 1.5 mJVl
ro... .' )lj ,nt'", I..,
n ..· tI,IlI<..1lu
"f ~ n 1'n
,.(..,; " .n i' I""1 kiu,ln..l.. ·nl tlM' !N'l ( ,li'''·1K.. li",ih
f.., II.., n"'l""" '" i,, :;n 1 n"a1."I>,...1. Ki" 'I1 II..· ~" ... ,10:..... n ..· 3-1 nM·ml ...· "f IltJlI, ldndn'tl, ilh II " ",. nl;l] n .. I"..'.......... il.. lil I... II-.:-' tiM' .... ~' il .. I ,..I 2.'j " f Ih. ' 26 I1M·ml ..· -uh " Il"\i.lillli 1l"I!"m ,,· illl" iu,1;,;...1,.. 11-.:-, tiM' ,,010 11....... ( Ho.. lr Tl f,u", ( rH"il ~'. 11.:\ .: S~~"I ...i" '" "n pllillTt,..... 'l(' ·' lit.. , G'·...1i<.' f...... I" ... in 11M' n"'I"""" lu II..· ur..! .."I;,;.t;&K',Ltnl ,Iml:' in
o 100
80 60 40 20 Percent Reduction 01Prothrombin Activity at 48 Hours
o
",,,,rt"
I"," w , ~·'''1it'S. I>TtI. ' ....lin~ "f tI..• Inlt-no,,· ti... 1;l] O:..tpo'M of lI " m"" G''TM-tit... 11Ih·rrul.hllllill C'''lK"'''' So·n.... 2',0 , :I,m.to·" L" n. E""'1 Jt;< ~1 .. lklt, 1972. PI' . .f2.\ -ll \.l
l'OllI(X'k s 10 produce Its ant it'll
PHINOTYPING Phcno l~pi ng: patients for a p articular IIIl'1al Kllk pal hway, sud l ,to; a('(·tylation Of oxidation. prior to d m R administration has been p mpost'll llt'(l lll'ltlll til t' m ho of dr ug an d Ilwt a!ltllih ' conceru rauons in urin e follcMing a si n~lt, tl Ost' of a markt'r. SIIIEllllt't! 'azilll'!Ht<; 111.'1'11 II ~ ..I to p lw nolypt· for slow 'K'l·tylalion; ;11lt1 spa rkillt', for slow oxidation i,m ,l\ing:dt'hristKluilll' 11)'tln nyl;tst'. 111is app ma{·h aims to lx-rn-r antieipa h' lhe c1osa gt' rq?;illlt'll of a dmg: n-qnlred in an iudivklual. Its appt.·aJ is gn'a l('SI ill Ih,lSt' situations ill whk-h: Ihl' therapeutic iudex of tilt' d n lg: is luw; thl' aual~~'s o f dmg am ] its meta bolites in p l.t<;mil an ' c1illk ult ; till' tnarkr-r is relauwly s afe. t'a')' to measure. and its pl lt'llolyp k d litnlt1t'ristit· is h ighly com-lated \\it h thai of tilt' d n lg:. » t'sp itt, its llppl·al. IIwtalltllit, pllt' lIol~l)i llg is 1101 \\i dd~' t'llIpIO~l'( l in di nk' ll p ractice, for lIlany reaso ns. Om' is tilt, mconvenk-nce a<;~)(:ia lt'( l with tllking of lilt' ma rke-r and lulll'<.1 ing uri llt'; anor lu-r is ;t<;s.a)' t~)S ts ; am i ~l't unot lu-r is ti l(' Ilt)Ssihilily of faist, positin's thai an' elm' 10 otllt' r tl lm ·ntly adm inisten'll dmgs, such us cl" inid int' , inlti!ailing: tilt' en0 11W. (;t'u ot)llillg. luee-d Oil D S A .tnlllysis of a small ~u Jl rl (' of " Il u l or all )' other IiSSUt', holds IIII' promtse of pn l\iding a ilion' direct approach toward pft't.l il1ing: 1J1I'1'lho!it, plu-. Iltltn ll·. Curren tly, D ~A tests have pn-dicn-d lite pln-notcpes for IKIlh :-:; ·at.'('lylalion and dt'h ristIClllilW h)'(IRJx~""ll i(J n in 9.'5 III 97.5% nf llt'ultlJy volun teers. wh id l d t'ur ly ind it';th"S the importance of ~t' l lt'tit..'S a.o; tilt' major sn u ft.'(' n f '~dri ah i lit~· l lt'n· , TIlt' .lpplim linll of pbe-notypi ll~ to pn-dtct d(J~lgt· dept'ntls till lilt' n 'latin' t1111trih u tion u f otlu-r factors. such .t~ t1i.st·ast' and concurrent dnl ~s , to lilt' overal l vari ahilily in d nl ~ uu-tabohsm in tilt' p ark-nt
population.
STUDY PROILIMS IAn ~wef$ 10
Study Problems ore in Appendix II).
I. G in· twu t'xmnplt"S t'udl nf inhcnn- d variation in pl mn tlat'llkinl'l k'li am i ph arlllac.'lKly. namics .
CHAPTER 14
22'1
GlNEOCS
2. I>dilw lin- terms: ~l'nntn)(" , ph ellol)lll', and j:;l'lll"tk poly morphism. 3 . Discuss brit,fl)" how lUI inht"rih"ll SOlln '(' of variation ill ph an n,K"Ilkiul'fics lW .U1 he idt'n · tifit"lI ....1thin till" !);ilil'nt populat km. 4. A xtt'min' llwla!lllli7..t'rs) inv;t"stt't l uue l,f llit' follO\\-11lV; fuur Jl-adrt,Ilt'Q.,ric hllll.'king d m gs: iltl'llUl()I , lIlt"lo p ru lul. pmpr-dllulol, und tauolol . Tahll' 14-5 list s the 1Ill",1II \1111ll'Ji of va riou s pha rllIal"llkindic paranu-n-rs for l'ad l d n lV; am i wllt't lu'r till' ('orn,btin ll ....-ith debrtsoqnnnslatlls was weak or stmnV;. l>iq:11SShrit'fly IXtssih ll" n'usons for lilt"(l1>""'l'\l"(l corre-lations. ' ..... 14-5.
a
"'", 50 63 0 50 0 31 0
38 2Q()
280 150
, 3 0 .0 <03 4.7
fl. a. G in' h \ll esampk-s. ill add ition to lIlt'topmlol ami tillluiol. of dmv;s that an' m.idi 7.t't1 and that f'xlaih il V;I'l\I,tie polymorp hb m in the-ir clearance. h . li lit'fly di S(1lsS each of til(' fullo'\1nv; stan-nu-uts: L F h-camkh-, an au ttarrythmic aV;l'ut (ff' "" 0.4 3 1. is" suhs tmtt' for Ik h risollllil1l' h),lmX)-la.st' (C YP2 Dfl), }l't nnly in IMtie nls '\i lll seven- n-nal d)'sfulll1illll is V;t'nettc POI}l llOrphisllI in dl'
,_'
15
AGE AND WEIGHT
OBIICTlYIS The leader will be able 10: 1. Desermire eose drugs for which Iooding dose. normalized for body weigh1 , is likely b be independenl of age, given the volume of distribulion and fraction unbound 2. Cesaibe the likely changes in the pharmoce*ineliCS of a drug Pfedominonrly excreted unchanged. from neonate 10 elderly polienrs 3 Adjur.t. based on age and weighr , the csool adult dosage reg,men for on individual oIdef than one year of age.
A ~II ~. chsracn-rta-d
bypcnods of WtM1h , t!t...·(·lnp lllt'ul. ,lilt! '\(·lIt·S(...-ncv, is a n additiona l souro- of varia bility in d n 'g rt'slxmS(' and . ;L~ a res ult, tilt' usllal ad ult t10S
A POINT 01 RIIIRINCI T lmm glJolit this dmplt'T n -fen-ncr- is made to tilt' "( usual] adu lt dnsag,· n'¢ IIll'Il,- I~'fon' procecdtng. this ph m_'i(' needs to 1)(' ddillt'tl. TIlt' word at/lilt refe rs lu-n- ttl ti l" typical ad ult patilont\\i tll ti ll' disease or condition n't illi ri u~ tilt, d r ug. n it, "( u sual] ad ult dO~I~e rcg tnu-n" is dt'f1llt--d as that rt'¢IIll'1I wlJk h when W\l.'l1 to th is f)llk'i,l p atient O!t'hit°\"(·s t!le r.ll)(·utk S llt:t.'(-s..~ . Clearly, the charact e ristics of tilt' adult patit'llt population d ifTer with til(' t1i'i(';L'i(' IM'i n~ treated. AgtOis t'(ortlti lily om- of tllt'S(° characteristics . 230
CHAPTf ll 15
'"
111t'(Lito, in Fi~. 15-1 , !l I M I diffen-nt a~e trends for tht· II ~ ' of hm d rugs. 11111\. p"lti" IIIS lakin ~ di ~()1(ill . IISl"(1 to treat l-an lill<.· disorders, are ~l'll(' r.ally nld" r th an those takin~ nitrofUrd.nlo in . 11...... . 1 to In 'al urinary tract infN.-tiolls. a condi tion m" n ' ''''' '111)' alT('<.-tin" JX.....p ll· (If all a~, .,. . l'atit>llb "'i tl. in('fmlin t·IK"l.· an' V;(·lwr.ally '...·1· 11 ohk-r, 70 to Ml )'f.·ars. than IhoS(' with cardiae disorders . IIfM, ...·N. there art" ft·..... tlm~s fo r which t·,h ·usi...... Ilhan nal"ukiTll'l ic data a n- uhtailll.....1 al the mean a~,· o f t t.(' ad ult pa tit' nl po pu l.d iull. S i IK 't" O K...I patien ts takin v; dmj..~ It·lltll" hi· middle-aged . fo r Ihl' PUrpt N 'S of sllh....... IIIt·1I1 ('".".It'-Illations. all ad ult a/o:t · uf 5..') wars is iLSSlllllt....1. The- tlaia in T alllt· 15-1 illustrate a point ahem! a~t· and tli...·a.....-. Li,tt-d an' t'Sti lllaft'S "f tl.t· p" pulati o n rhanmtl·oki'll'tit.'s (If lli ~(ltill in a ~JCJp uf )1Mlnv; 111",,1111)' a
Nitrofurantoin
t·l lt. I S_I . .' C" tI•• lnh u l lOn fir tlruc ...... . umpUon . UutpaU..n ll In
50
I.... IUln~' "(Jlml l.ntl. S..... ~"I>. I.d. I~ Ihcu.. n an' ~. oIo.l.·r ltwl th,"" t. h nc nilrofur. nloin. I,' lt, trat'lr tl fr om Borlhiu• . <: ..nd S,....;d. ' c.: I), .... .ntl cJ,~ lulri"
40
,.,J.
......"....
..,.J
ph.um"""lo:.inrhc pli nctp lr,. elm . PIl.u m u nl . Tll rr.• 2 "25.\ -2~3 .
30
IU7'l )
20
15-59
6lHi9
70-79
, 70
Digoxin
30
20 10
o 15-59
6lHi9
70-79
veers
, 70
232
ACt: AND I/VElGHT
CHAI'T£i 15
,.ltJ. 15-1 . hp.I.tI_ PIIa,..__kl_tl. h_ rs .. DI••• I.I_ Y__• H_....y ....Iem ..... l.. petI..... With ....... C.....HI•• c. c•• UUN
Young heolr+.y SUbJe.:::tI" InPciloenb ,
2B
71
54
68
40-70
7t/J
85
J5
476
3.5
14
-..ere
"""""~ ceooc 10.....
i llpa til'Il t5 rt,(" i\;I1~ d i ~lJ\ i ll for tn-atun-nt IIf s('w n.' l111l~('st iH' e.m lial' [ailun-. l\'ntit" ,!It" di lTt·fClIl't·S in till" values of tilt' ('sti malt's , [l'util1ll;arly fm n-na l dt·ar.lIll...-. ht·· IWt't'n lilt" two ~rllllps . E\i dt·utly. t'stim :lIt's ill till:' )lll lllK Iwahhy Kmlljl an' of littl,· tln-ra-
""rnmll uf
PI·uti<.' value. Part o f Ihl' difTt'n'!w(' ill renal ch-arauce of t1ig,nx ill h t'! WI't ' 1l tltt· !\\11 g,ruups is ill'(."l, llIl1ll'd for h~' the t1ist.' lL'it' , Pa rt . h OWI'\'N . is al1.1)IJ nlt 't l for 1Iy aj.!;t', O il(' ohjt'C.1iw of thi .s d ,aptt'r ls to SllAAt's l IIwan s o f 1''OTTt't'tillj.!; \"alut,s of phann,wokhll'!i(: 1)
PHARMACODYNAMICS l1mmghont this chapter. tilt' m ngl' of unbound plusmu d nl ~ conwnt nuious ;t'iStll.'iah't ! wi th s lll,('t'5sfll l t l l<' mp~' is assumed to hi' indcp-nch-nt of a~t' , Fur alltie pilt'pti<' dnl ~'i alll! t li~o,'(i n , l' fft't1i\'t" plasma d nl~ t'UI\('t'ntm tiuIIs aplx'a r to hi' the SiUlI<' in Iltlth chtkln-n and ad ults, alt h(l\ l~h cluhln-n "PIIt'iU tu tulerute a " i ~l ll' r c unvntra non of tilt'st, dmgs lx-fon - ;Ul~' tone mamfestanons IX't'(IIll(' ilPllilrt'nt , Difft'n '/lt'('s in n 'sptJllst' with iI~{' an ' likt'ly tn (''(ist fur certain drugs. Fur example, th e ohst'r\'t"d inl'J'('il'it'{! st' llsiti\ity o f t'ltIt'rly Ililtit'llh to tilt' ceut ralue....'(J\lS (,fTl't:1:S of be -nzodluzepim-s cannot 1)(, expl.uno c l 011 ti lt' hil'iis of di ITen'lIt't.... ill pharmacoktnetics of this ~n lU p of d n l~' ,
ABSORPTION D n l~ absorpnon dllt'S nol ilppt'iU to dl a n~t' dmlll"ti('lilly «tth i1~(' . :\'llIw tllt'l(,ss, all tilt' fadoo tIiSl'lls'it't1 in Chap. 9 that aITt'(1: dm~ ahsorpttou, indud ing ~,l'i l ric p i I, ~il"t ril' 1'1II1lI)ill ~, iute-snnal lIIoti lity. and hlood f1 uw, do d l
AGE ANDWElGHl
233
n 'ry yo ung. Clnldn-n "rtt'n app,r-ar to a h:-Clrb d rugs il-~ t"l,Jlllpll'lt'!y uud. if an~t t.ill g , mnnra pid ly than adults, At1:'o rtlingly, in subsequent calculations of tlosagt', e xtent of absorption is ;I-~s u med not 10 va ry \\i til agt'" A major exce-p tion is for souu- high fjf'i l- P;I-~s dmgs ~ n 'n III till' ,.Idt·rly. II t'Tt, ural hin
BODY WIIGHT Om- ,l-sp,'t"1 of a~n.l: is IMKly wt·ight. \\"t'i gh t, 3.5 kg at hi rt h, illl·n"I-St.'s rapidly in l·!Ii1d luKltl
and atlo l" s(1' nl1' und tln-n d t·I:lint·s slow ly in tlw t·ld t·rly ( Fig, 15--2),
HI'(.~ l lISt'I M lt ly
«un-r
' 1);111's, musck- mass. o~all IIllM ltl llow , a nd organ [unction art' related to h'ltly \H·ight. so too sho ul.1 volume- of tlist rih lltioll . clea nmce. allll ltt,!w(' d nsag<.' n~lI lt'lI S uf dm,gs. (}.\i ng to Ia~,' \"aliahilily, !towt'wr, a \\'t'ight adjustllwnt is ~ellt'rally thou gh t 1I<''(.'t'SS
LOADING DOSE Cli ll i(·
huling dose proporttonally for Iltltly wt'i~h t appt'a no n-us.f lllah lt·. The vuluuu- (If t1isl rih ulinll 11,1-\1,<1O il unbound dn lg. \ ''' ' is fn 'qllt'ntly IMlth din'l.1ly pn lport iun al to Iltltly wt' i~hl a nti il1Clpllt' ndc'nt o f agl·. hilt no t alwaYli so . ~ l lldl t1t·(lt'llds n il til,' ph~ ... i( ,.c.'I ll'lIli(~11 PruIM'rti c's tlf tilt' dmg and Oil tln- n'usou for IIIl' di!Tt·rt.·Jj('t· ill w<.,igltl. Show n ill Tah ll' 1,')- 2 an.' valm's for d t1'"'1' u f plasma pmh·in hill cli n ~. vnlunu- uf d i.\ tli 111IIioll (V). IIl1lMlllllcl \ ohunr- of e1isl rthution (\'11 ), a nd percent o f drug in tln-litltly unbound, for u 111111111(' 1' o f tlm,go. in m-ouates and adult s. 111(' h st 1\\ 1) Ilill"d Tlll't <.· rs w e-rr- calculan-d
70 60 50
"
"-
40
E
.~ 30
;:
20 10
o o
2
4
6
8 10 12 14 16 18 0 10 20 30 40 50 60 70 80 90 Age (years)
FlK· 1.'5-2, \'. n"I,,", in "",r"I:" " " il:l,1" illo "1.'<'. fmlll II.., ,..'" ,\a !o' In II", ,·I,Ie·r, WMId,1 ilM-n·.... ~ rdrmU~' in tI.., ,[" nlll( II.., fi n l ~" "r Ilf lif.·. ..", I,IunJlI( p',I...~·. It ' Ie....ti"..... Ie",,,,,·..fce·r ."jll ~" iU"'I ul" "1(' " ( 1).. 1.. fmlll' U-2t1~ ";Cf'i. I " "-~ ",,,," I .. (;' ·h~...-. ,'!1f t, E,I.. Ii " -l. K;cfJ(l'r, I~. J'I'. 2.'5."j....2.~: 2tj...~ ~,·;cn, 2nd ~ ..li" ,,'" 1I"altl,
~' '''''I:, l"uhc.ll ld~
,,",1;\ Ulnlin" E' atnin.,Ii.." S"rw'o'. I!f.'fi---.'ll l, ~1 ;c -LIIl' 1. U ,S. ~ ..liu..'" (;"nCo'r fur 1I,·;c.h l, St.ti. lil's: 7S-~ 'o'~'on . cue 11"",I\... ol" f , ..,nli,,,, in till' ,\ \t<..1 EcI'I,..l i~ a.n. Wal" "I, t1urilL.. CIlI: I'n~,. I ~. p, I ~.) ,
CHAPTE R15
T.It•• 1
2. Pl._ Pretel. ai_I....... DI.....ItwtI_ D.t. .... s._ ~ .
I. N
ceo Phenobo
SuNiso_ozole
-"
SuWa~az,ne
Digo-,n
A41."'-
. 1'>fON.loH
068
0 .32 0 ,43
0.80 02
"'" 0 53
,o..,t()N.>.ll.
"'" 0 ,55
0 16 0 38 0 .70 010
3.
0 .16 0 24
to 0 .47
t1.3'O
7.0 0 63
~" 1.4 1.2 1.1
is 65
"'"'0
1.0 063 10 6.3
r-.l0\lA1E
1,56es 72
t 12'2
"'"5.
5. 02 6 0
from III am i \' ( ~'(' Chap. 10), As co mmo nly Found. plasma binding is lower ill neonates than adults. Yet , for tilt" first tlm'(' dmg.s, plu-nobarlutul ami tilt" two sulfouamides . \ '11 . corr ected for hod,. \n'i~hl, is the same IN.''(~,llI~' must of Ilw d m~ is unbouud in Ilw Il(xl,.. Clearly, for tllt'~,
....tth total body wt'i~1lt.
DISPOSITION KINETICS Fi!!:llrt" 15-3 shows d J:lIIK('S with aKe in half-life ami dt':lnUll,(' (If l.' n '
AGE AND I;'oI£IGHl
CHAPTH 15
23S
(Maintenance Dosing Ratelkg)/ (Maintenance Dosing Ratelkg in Adult, Age 55)
or (Clearancelkg)/(Clearancelkg in Adull. Age 55)
Hatf·lifel(HaIHifein Adult. Age 55) ( ..... )
(-
2.0
)
, r
,r ,
, ,,
1.5
1.0
,, ,
i
>)"
I
,------
0.5
2.0 1.5
1 / y'
,, , ,
2.5
, 1
"
1.0
_ _ -- - -
0.5
o
0
o
2 3 4 5 6 7 8 9 10 20 30 40 50 60 70 80 90 100 Age (years) Infant
Child
Adult
Elder I~
Neonate Hit. 1$-3. " " Iwlf·lir.. (I.·r, ..",I." da."N'tlli,... 1 a'Hl lHllIo d"a r"'I(~ ' "'HI "';4i"h ·n..,...~ · '....ing nil.. (IiW'1 ...",1.'. n"',"" l lind ..f lnlR miw,l "1U)" ..i ll, "l(l' . n H' "',.]' M" ..... n · .",10,,1.... ..1 rno", .I..t.. "n •·n-;dini'M'. 11M' , In,~ lik.· .T<"1Olirn '... . ,1" l nl." I... inlo I", .,] IH"~' .. ;aI,·r. i_ 'H" IH""HI ill pL._"... n r Ii.." " , 1 is ,·litnlflllt,..I ,·nli~~· I~' n ·n.,] .-uTrli"n ..i l h .. '''1''..1 ,,, tI... ~" tH ·mL.r liltr..li" n nah-. Ib lf·llf.· i po I ... .. rnM.'tin.. 01 11..· a r.. ,,.\.... f" r a ~pK"\ .').'>-~...a r..,j' lllIlu h 1", Iil-nl; II ~ . ..'!tin....' i• •...k~'I ..I I ..n 'lIl1inR lhat It... d.-D....I ·T'lOI:'· pl"I""" unl. ,,,tHl n.u·ntr..liI" main...."' 11 th"' '' 'RIH",1 lir.> . :",..i<.... llut. I......" ..· " f p""" r.·na l flllH:ti"n, lwIf I...· .. I"h .·limi' WIH >1l i• .I.M' ill tI,,· ,...." ,.., 1" ,1 i"'p"' ., r"l"' Uy ,".-h 11,.1. loy I ~,·ar. h..lf.M.. i. ill ' , 1;4.,,1 10"'.,...........·. II ha lr.lif.. I... ~"tH.. I<"' R.·r I u..• d....nt1 ..'t' fttt 1iort tlf s..rf...~· , ,.\,.... n" n nR d'il.lI ......... in. ·n· " ...m · ." ~' with lQ'....lI, t!w , .1.".. ".I"n..· tlf d i.llih.. liI,n f", ...1"'''' "f I " ,,~' ~1 . All"'''' ¢> I", ,,~' .. ~-iRl '1 1tl...n ·f" ",I ..",.· "f ,li,lli],lIh"" d nl...· ""J:.' .1iRl,tly 1..~""t1 .1U ~~."",. h:alf.lif.. I' 1<"'I:"r i" II..· "l(l"1. I. ".,,, · n ·,...1 i i.." ..,..I tI..·,...f" '1.•..,...., p n ",n...I"'''· .Iiminhl. , H~' \:I.") ~.""" h:alf·lif.. it twk't' II... ~l'ioU 1,,11 ,,.\..... n....,.- d .....I«'f. ill d.~..n ~·ltl .. I " .· id ,l wilh "lot.· .'~p"'in .. hy ,1M ' nlOlin,,·f\lU I.... r bl<",r;4tt' lOr Ix,,~- ·ld.t i\ hiRl"'r in Ih.· d ..kllU..1k ~·r in I h II · ,.........I t· .. ,.. I II..· ..1, 1II",,, in I • l"lt , n Ltl.. 01 1in I...· .Olk~ ll ..t"'.." .. . ·n · <" ..,uIl<..I f,.t" "I: IIa!f-lif.·_ ..c al I..I'..1 f" .." ~'''llnM'' "f di.l rihllti<.., ...",1.·k nt1, lI ..1f.lir.· i" lUI "''''''Jo(l' ...Iull. 55 ~"..n . i• .'i ij hr. \ '"1",,..· " f .h . ,ril"lli<..,- TaL 711:'1- " f I.,,~' ,",MRi'1 ..t "'rth. !'i, '1- "f I.. ,,~" .. ... fi ). CI....rantT-Mi hirt h, t;J..." "" f"'''1it", in inf..,.., · anti m l1tll 1 .'u" . J. .... inu lin <4<...".,....... 3 ", I) m;" (\ \·MlI. W,H.; n ..· "\'",Ii"" of ,-"..I. Sd.. 229:6'~ . 1ij.').5); I ~ ..·n fi I 20 ~~ k"lL.h.. II~· mullip~i nK Ini · d.· , -. 120 rtrl/ml'Vpl'" I." "I''''~ nld "R III . " ...~.~. , I...... h h~'. ~ •• m~ 1.. 11 " f 21-29 ~""n. hy I ~" " .rf.,.'1' '" rnm , t 1...1.. " f Sitonl"" ·It.:"io:·I...·n (Sit·n ],ao:·It· S i..l...... K.• 11"' , 1. ' _M .• K"''' I>I" ......~ ..·n 31101,,,1W ~.~" ..... m..nn . J , 1 Kri" ...I,,·n. M,: futpio: l ,.\ " .. tio: II' " f ..... ~"I"' i ...· d'~"""'K't'. 1 ,....1 . 1:1133- 113-1. lij'j ll. s "rf...... 1./'1 "lit"'" nlf't..n · [Wl"iKt,1 ilt)tll An...__Cal d..I•..J f" .." I."i;.- ......Jo:hl " .,jnl: 1...· n-1..1"'''''''ip: Surf"''t' ..,....
d..........
I,"·
f",..
W.,
''''''I''''J'I"...
""",tI" ..,..
t"",·"
,01'" .
'36
CHAPTU 15
Mo les .
Cr&Qt iolM
Clearance (mVminl - 11 40 - Agel "
Weight
70
Females .
.
Creotinlne Clearonce (mVmln) - (1040 - Ag e) "
Weight
8S
2
when- a~t· h cxp n -sv -d ill )"l'ars und .... l·i~h l i ll k~ , 11m..., ill an lIn 'raKe UO.~'{'ar ..old. fin. k~ adult , ck-arunce-s (4.'1 m l J min. mall' s; ;}.'5 TJl IJmin. (('malt's ) art' ()"'5 tlnu-s those o f tlu- tn}iu tl 5.')-yt'ar+(,1d !);Ilit' n ls. wh ile t lu- VU]II('S ill a 20.p.·iar.old, iO.kJ' ad ult ( 120 mlimin . malt's : !02 1111 J ll li n , ((' malt's ) un- I A tum-s tllt ·S(>values . Mon- Kluha l rt'latinm hi ps that Incorporate scrruu cre-atumu-, 11 rt,1I1'1..10r o f hotl. l'rt';d iu irw p rod ul"lioll a m i n-nal excretion . i LS wd l a.s a~(· . " ('ilotht, anti ~1· lIdt· r. ar t' WVloll ill C ha p . 16. BI'l'iIIlSl' to ta l lMMly ' S111N a-s II percem o f hody \\'(' i!-th l. und lu-ncc d isl rilllltioll. dmll!-ttos rt-Iatin-Iy Iitt l,' t1Urilll-t lift' , Iht, I,:h;Ull-tl' in cn-at lui m- half-lift, i ll\'(, rst:' I~' rt'fI'"(.1s lilt' dl;lIl ~(, ill d .'ar'lIIll.'. That Is. tln- Imlf-lifl' is shortest unnux] I )l 'ar o f a~t'; il is 101l ~t'st in hoth 11' '''\'''0 01 alld ,' ltlN I)' p anents . Altholl).':h t'xli'llsi\'(' d ata an' lal·ki ll ~. simila r ago-n-lan-d dl,IIl ~" S ill di sposition uf d Olj.,"" st't ' lll In (){'1.'U T. In m-wlsorus, creatinun- d("lr.Ulll.' is ('\"( ' 11 IIInn' depres sed per l';I()~ralll o f hu(ly wt'i~h l Ih;t11 ill fllll-lenn Ilt'tll mli's. C n'a linim' dear-lIll't' aplx ';ITli 10 increase l'xIXlII('n· tial'" bva f,l(1n r of S !It'tWt't'li V; ,Ulcl 40 \\'('t'k.., ;•.'; s1l1l\\1I ill Fi ~, 15 -...·, . 1111' d;lhl in dicate t1lal l'~'alinil\(' d earalll't' dllrin~ Ill<' first few weeks aftN birth is pn'1.!il1t'tIIl)· comx-ptlonal
,m'"wI"'"
100
~
p
~ ~
>
"p
80
-
~
2
.~
2
~
"'j;'
,
60
,
-
-
~ ~
" 40
e,
E
~
e
•
Cardiac index Glomerular filtration rate Vital capacity Renal plasma flow Maximal breathing capacity
~
e,
20 0 1" 0 30
50
70
90
Age (years) t"i!t. I ~ . \t ~,,~· pt .~,io.J. 'l"<· r'''.di..,,_• •L", i"iu , ""tI. illt-n-,,-.i ,,~ ;&~. dllrin\( ...1,,1,11 1 (" ....ph ...1 (ru," SI.. It-~ . sw., :"j(" d liUl!o:''' ill p11~"')O:oIo ~"'] rllllt-t io.." . ill , I..· 1,,(;0] ;&ni ul;&]; n l<' rule· . ,r Ii." t-..bh'l.l I ~' B IR Sl rd )!.'r . n .., hio.... '1{\ "f ;t(itl'o(, Wll-.I'i l~ '''' . (l ,c. , .-,,,,It'ric...tI I". hl,," ·
231
a~l". (finn - sinn ' l'Ulll't·ptiu u). I)usill l{ requirements for a d",~
that is primarily excreted
1I1ll'hangl'tl d l\ ri ll~ thi s period lllay be approximated Imm knowledge o f the conceptional al{t'; hul IIIl' n-quin-ments. RS rt'll('<.'tl't! hy creatinine clearance, an' rapidly (:h a ll ¢ ll~ and
must IN.' (111\tillually updated. :'\(' xl, ("llllsitlt' r th(' duta 011 diazepam , a d m~ IIll"taboli1.t't1 p rimari ly in the live r. As S('C-'II in Fi~. I.'>-fi. diazepam half-Ii fl' is If)II~('st in the neonate, particularly within the first few da~~ . ami ill adults older th an .55 yl'a rs of a~l·. Infants eliminate tilt' drug most rap idly. With cn-annhu-, tilt' Inll!!: half-lift· in tilt' neonate is caused by depressed renal (UIIl1101l. which
100
•
•
10
. '111;_ 15-.5. Cwa tini,
o 00
d,.;ln",('1.' ,
k.. llln'
;",.1k",,·r ." ...."5. t .......I....linn. ..nCL..( m lJminfl. 73 ", I ) • 0.37 3 ..0 Il l ' "«' a nd C I.... ( m l.lm in} _ IU MH fi2 .. 0 1111 . " . ' , rt"s!"-clin" >'. t:...· n ..f,.., (",uN1;" !: for . " rf;oc.'t" all'll, clo:'ll flUl("l' i. jtTl.... J:,' tl.l'n ....J "'p'..:;;"II" tI" ...· cor rin ..... Ii e r ('<"'('< 'p h" " al "It" , R.'(,..lI lh",
o
"'''IM.
l......hnillt·
0.1
28
32
36
40
d .." r.ux.,
(m m
6 11"",11••
' n 2U ' ,,".of' l. ;d U ll 120 mlJminll .i3 ml , (AtLql'l ...1 (n" " AI·Il.."'....,,_ J.,
" "J""l('k. G .8 .. C hant 1,·., C o, <1", 1
44
Stim",J.·r, I ~ , Sl.limn I" M'.....I".; ' in
Conceptional Age (weeks)
,..n n Iln d prt1t·nn ,,,,\,,,,,1<,,,, An"h. Dis . Chilo!., .'io'L]'1.~2. 19'13.)
80 60
20
o
Premature Full-term Newborn Newborn (3-30 days) (3-30 days)
~
Infant (H O months)
I
Child (2-11 years)
Adult (20-55 Years)
Adult (5H O years)
H lt. 1l\-6. 1I ~l f·li f, · " I',h"",'Jl;nll!: !>L\p"' iti"n !>llrinj( 1>..",,101''''' ',,1. ~I"" Yorio:.. Sp' ..:.1 n ll" !>uhlil...li".... 1977. PI' , 3 11_lfilh 'lI l l'_-&.')6; ;1,,111 rn"" II.., ,L.l;l, of Kk>l7. U.. .... " •.111. G.R., " '~lm l p" . .'\ .. Sd ll '" lw r. S.. 1100 W ilkin.. ", . ( ; .R.: n ..· ,·1T...1 or '"!-" . ;I,'lI l liwr IIi......." · till' Ui' I" " i til '" li min,,tk,,, or ,Iianl"'m in ",Inll "'li n, 1- ( ;I;n ,
'II'
In" "\t ... 'i.S : 3-& ';'~1.'iij. HI,;,:,>,'
II,,,I..
231
lalt,!, "<"'t'ml IlIlIllths In mature. \ \'ill . t1ia7.t',l In"".....,. a point 1II'lllt, (';arlit'r: dlR lllul(~k a m i flllK1icma i a!tc' must Ill:' t lisfinJ:uhllt'tl. t""pt'liall)' ill Ilt"Ollah-s. 111l" shnrt N h.llf-li(,· (If tlia:t.t'pa lll in tlK' infant than ill tilt" 20· In 55-)l 'ar-uld ad ult n-llects dHTc·n·nn.... in dC-anIl K'l' pt'f lilll).,1T".Ull. h,,"('".I.IISt., \ullllli(' uf dhtrihu HolI of th is d n l~ is ap"" p m \ illlillt·!y tht· SdIlK' 0 .2 lAJU in 1.0111 Wf" lps . 111(' further prokm!talilJlI ill half-lift' in tilt' 11l1)',t t·MI·rly ~ml l p , dl·:.l.rly !lIIIMl l to l it-, ege- n -Iate-d ( Fi~. 15-i). requires !>C)IIlI' Ih!>l-m~tOIl . C I,'ardIK't' n ' lIli1i ll~ t'S"'l'llt iaJly constant . and \ulUIIlt, uf tli!>t ril mliu u h ilK"n'a"'l"(1 ",ilt. a~' from 20 In MI ~"iln, bill nll l~' IJt'("auV:" of tiM' 1t"lJ(It'IK, ' for KM't' r plasm a himlinJit of dnJ!'t. l)i.w.1l;lIn i.. admit Of KM'I"'ltrM:iiull and lary:" \'oIUlllt' IIf I li ~t rihu tic lU , aIKllx"t. its d l'ar.uK."'(' At"t1 inJ: dilllini slK'tI C'".lp'I ~' m .idatiou. For t''-I lIIpll'. thl' d t'ar,lll(,,(' ( P""(lc ll ll i nan t ~· nn-tabohc} o f lIntiP:oTiIK' , a nKJtld t't)lIIptJIIIKI Il_ 1 tn a.~\ol"'!> lI,t' ..tat u, tlf o, icL ti\1.' IIwt al. )h...m in tlK' hve-r, tlt"{"'rt' il.I>' 1% l"M"r >l ~.tr ( Fi ~. I5-H). II cJ'.'1"\1'r, tiM;' n\ '(.' rolll \1lriahilif)' in U1I;kl l tiw d C'il.roUK't' o f I l n l ~ i~ lI\u.llI> LlIl~t" :11I11 a., \\it1l all t i l"~Ti IIt', ~t' ma~' C"dpt u n ' nll l~· a s mall pt ' n't"nt o f tilt' hltal \Olri.;U K't' ill d l'am.lIl't'. Ctmju!:tidht, l-olpadf)' also dec n -ases hill I~' a It"!>.'\t'r 1'\lI'nt than mt Ilatiw l'4lp,lli t~·. 111t'S(, dlan Kt"S llIi1.y 1)(,' a5..'i()(.i a h "(I, in part , \'oilt. Iht , t1 t"(·n.·a.\<.' ill tht.' StJ'.(' o f tilt' live-r. a.\ a p",pnrtinll nfl:XJtly \\1.'i~h t , from 2.5'1 in the >' )111I).: aclnlt lu I.6 'l ilt 00 ~l'an uf a~. ,. Fur \( ,11I1' lI\('t.tlx,liJ'-I't.1 tlnJ~ . no d ';lII~t" ill dt'ardlK't' or hal f·lift' ";t~ he-t'n nh~ 'I'l'( l in t h., dtl,·rly. Unlil lIIun' data hC"('OIUt, il\'a itahl(" tilt' I Jt~t current I"l't.lk-tion ts that I1It1ilhohsm is I,itllt'r dt '(:n 'il-\("(! or nc" dlaIl RI"(! in tiM' t'1dl'rI ~" Tn he' nil th" n )IJ!iI' I'1Iti\t' ~ille uud
. '1([. 1:5-1. n lt·lwJ(·!lf.. ,,( [1;_ ,...... illI""lI-'l ~ .. ,11, "1<:1'. ("'''' 2u 1 1~1·"". (CC ltll, I.· ,LI.. fn.", I .~ KI"" . lJ nl. Gil.. "'~1" n, A . s..-IIt·"t..·,. s.. "'I(I Wi l ~ i " " ,. ( ; H., The· '· fT....1' , M" ~' ..,:xl Ii..., ,b•• ........ "" 11M' .1"1.... ;lio '" ..,"I .·I" " I,,"'io lt' of diu~i"' rn ;n ...Inll J eli" 1" ' ...'5.h'H7~1'1j. l ij;~: (,..I·
1m",
.. "'CII~,,.... nit·.." "'MIr.."" ).... Cn'C'C,I>L.l1 . IlJ., .\ lle·... \ 1 n.. lI ..n "..I ~.. J s . "'MISh..ttc.... R l : I>i..,.,..u" ,b•. pt .. It,,,,, .1.·..·. "" " .."1•. 1.:1 1". l'h .. r", .. ('C ,I. TI... r . . ZJ,.31 1 1 ~1 1 2. 11j';'U, (OI- M..·tc... 1. S M.. <:,tc... I I <:.. IIo·" t.:'·r1. II . 1..,1. t' 1 So·ltc·" . F: . ~ I . : AK'" "'KI K"·,"It·,....L h..I.t.fTr n·,:x,,, i " ,1,_, ...", ph;m"....li. ,..1..... J ( :1", 11....,.,... >1 . J~ I .'i- lij. U,iY, ,. 1-\t..·U,....·. \ t·.. H..u1'N I. \t o J ' N O . ..,:xl R...... b,u . \1 n.:n l(' ..fT.'Ci ,M" ....... " " II pI m•••,,, oliflC1k"to of
•
120
-e..
•
• •
80
• •
•• •
,11UC'w," e lm . :'id .. S!i .f7lf-4 'l3. lIN).)
o
o
20
40
60
Age (yea,,)
eo
100
"9 a nm~b approxinmt km. tln- t!t't:lillt' fur IlUhllilll
i L'
a~c should h('
:'\1'\1 (umid!"r till' ilwn ';L, i ll~ ratio IIf platt·au ptL\lll
c.......
3
IDo../ kglh
it follows lila' tht, \ \ '(·igh l-t."lITn '1:1:l't ! d l';lr.lIll't' llIust lit" higlll'r in a )l Jtl n~(' r and smalk-r child . All lh('~· alllit'pilt'ptil' IImgs an' (·\tl"llSh-t 'ly 1I1(·taIXllii".('(1. allt! in 110 11(' studk-d tlc ..-s
pr otein himlin!!: appt'ar to dian!!:!' \ uhs l;Ultililly ht"tw('t'!l th e d ifTe n 'nt age J?:n mps. G n-ater I.t'll;ltie Illd aho li(o ("I Il
'"E 70
~
80
Young
Elderly
(13-37years)
(61-84 years)
tilt. I S-It,
•
E
•
60
c
'" ~
.e <..> u
c
~
0
D
c
:::>
E ~
~ ~
.~ c
50 40 10
•
iY
••
•
Male
0
•• -1L
,=.
10 Female
>fv,.'(·"
11."..
••
----:rb
30
,Ii"", ,,,m
·,,"LI1.
••
• •
U
""'iI..
n", It.. , n,.. .."h..H I " nl... ,"' I ......ar...... • i. II..· pri. mar)' .. ·a."m for il pn ..... ~ ..1half.Iif,· " f .1""0"1"'''' ill II", •·... It·rIy IlooI.h.·"I. ~ 1I ...Ir..",,'(, fn'''' (;,.... n J.... Ikoll. \ t o .. 1I.m"..tz, J.S.• ill,,1 sl......·r. IU. : I>i_"..m ,1i"!.. ..,,;l it.., ' ..-i......"i f1llflh C lin l'ha n n" . « 01. n,.., ., 2,:30 1~,) I Z. 1!:H1. "1,,..,,1 "'i l h I"'" Ini"it", " f C .\". M".I"...l
~
~
n., 11I,1."",,1(-!o·" r..r.. '(· " f
i. ..,,1,.......1in " IeIc'rI:-' 'I. ,'O,",,,,,..,,1"'i lh ~"" ")( ;O[I Il1t~. !>iIT.....·,..'(...a1"" ,...ht I.. m........ ar.. t f...
Male
• •• • •• •• Female
flit. I ~. n,.. d'·llr..'''~ of .."Ii~-n, ..·. ..n .....
80
Io·M;".·~' n,,-ial...Iilt...1,Im~
......1i.".. 1..,1 "'llf'JCin.
aiI:-' wilh II!:, ' ",l""l 010..10...1in .107 I"-,"h l,,. ."I,jt'l-i"
.....1, "f ",1."0 "",,'("i\.... 1 1 II: ;""l il~1iIlt· 1.\'. ,,~. "" • .." ",t. f,w lillie- tI( tI... ' "IlriJJlihl)' in d "OIr.Ulotl· "'illli" ,Iii. p"p"l..ti .",. (A,la pl ,.. 1f,. >ln \' ,'. 1011. R.t:., ~ ,,"b, ,\ .11 .• Tnlli". J-Il., C"I,,·n. B II..
s tu :!.. S ,W.. aI..1 A,..ln.. . R.: A nli!'~Ti ' ..· n,,-i.J .. "Ii.", in "'..." I " R.......... " f ~. llk"'.. ~ . r .Jf.-i.... . ant) on."'i"ll:, eli". 11",nna-
o
4.12. UI':"S .)
o
10
40
60
Age (years)
80
100
..
,
Jo"I.It.
AGf: A!'IO WE IGHT
I ~ I O.
("' Mil
(;,,,t.o,,,,,",
I. E .. ;uKI 110·,,, "1 ,
1-1':.: ~"'I" '1"'''''': l1.... n".... "':-. ..."' . it., ;tn,1 r/...n ll * "a,in.1it .". E,p. ( ;'·r·
•,,11,,1..2!i:4.1 '-H-1.
mj" jo,"
35
1'6.. ",,, ....·ar..,I(~· of
..Jf,·nl;t"il ,10."," ';0.,,"\ will, "1:1', 11.., ,1o."l'Tt'''''. ' i. ",,,n' l.n" '''''' I<~''l1 in f,·, ",..it'S k" I"....1cin-J.-sl ,1,;<" in 110;01... (" " '11 hLot'" cin,I. ..). TI,,' ,10.....•....• in (.." oak... "l;I~· I n ·L.I...1In l".-i, 1'.... . " 1....I " M.. "'1 "~ . l;at" • . I fU..J""""
(}n~ 'ldl
l~
Will> I,,"r·
'''' 'd
rmm
CHAP1EI! 15
30
• •• •
25
~ 20 ~
0
c
e 15 ~ ~
" 10
tl..• I'llMIn.....olin... iol., .J ;olf'''' '''01il, G,-".),-, dilT.·....K 't'. eli". 11...n n" . ...>I
5
•
~
u
IA'm"IC'''o, 111\1.• Ii" n ,,_ .-\ <;,1- , IIo·nni. , I'.J-. (;!.ltLllt'S, \U' I' .lt . .....1 Bl..;lI. J.C:.: Ino...·'....· ur ~,. ,>I,
•
•
. 0 0
o
...., .
• it> 0
0
o
-,
~
~
•
0 0
20
40
60
80
Agein Years
<:!1·;lr.III('(· occurs ill " 1mW Il h ut lI o l ill nu-n. 11 1(' dt'("n ';l'i(' in women lIlay l it, rdakt l to Illt'ir
1II1·noll;.lm,a l sial us . Furt her \~~ Jrk is 1I1"l'111"11Io t!e1e n nillt· l ilt' inll.l('lIn· of ho rlll lllJ('s ami otlwr f'lC.1l1rs O il tln- !!:1'lwm l h ·m lt·lJl·y fur mdahlllislll to
MAINTENANCE DOSE THERAPY Adult For musl 1l;.ltit ·uls, then- is g:t'lIt'mll)" 1111 m-edto adjusl t111s a!-tt· fo r ag:' ·' A 11(" '1l lllay ,·, isl when Ilu- d ifTt·n·!H.,\· helw("l'n t hl' indlviduul a nd tilt' l)lli(:aI path-ut t·\(~ '1"l L\ 211 yt' ars, fur ('x,;lmpIl' , in )lIu n~ ad ults k-ss than 3.5 )'t'a rs o f a!-tl' a nd ill Ihost' im!i\itlllals hl ') l md i5 )'l'a rs o f a~l', wln-n tIlt' I)pil'lll p,llit'lIl is 5.5 )'t'ars o ld . (:.c·mor.dly, {\(lSitlol;P is lIut dm lllol;'''l! ha'il.'11 em ~t· lld.' r . Th.· "us ual" ad ult d u'il.° is d t' ri\l"lI from dinil'ill silld it's in a lIlist"ll popula tielll. CClIl.sicI" nlt illu of adj ll\ti n~ for ~t' Ilt It'f IM'l'tII1lI' \ ilion' important ;lllhl' ext re mes, i.e., fu r ddt·rly wumen and )'l ll lll~ 1111'11 . As \I.(I\~l1 in T ,thlt, 15-.1 . l'f('atillilJ(' clearances of mall' a lit! ft' umll' .').')-) l 'llr-o ltl p,ll i" lIlS a n ' fair l)" 1'1 0\1' , bill a 9().\l'a r-old woman a nd a 20·\l'ar·old ma n tlilT" r 11\' threefold in tl u-ir t'n'atini m' d t·'lflllll 't'S. A 2<).)'l'a r-nld woman , !I0\ \·;...-e r, tlifft,rs nnly t\~~.. fold Imm t hill of a ~j(I-YI'ilro(,ltl mnn. \\'t'i~ht is aIS() a fat10 r he n ', ,LX lilt' awr;I!!:I' 20-yl"tfo()ltl man may Ill' do\( ' 10 7n k~ in \\l'ij.,(hl, wt.iIt, 111I' a\·,' nlJ.:t· 9().y to aro( lld wnuum is p mhahly on ly 6(1 kJ.: in si;r.('. TI l(' di ITt,ft'n n ' lIlay , ..... 15-3. • • pecte4 e-.tI.l_ .. "..... ........ A. . . .
20 55 Q()
a
...... M.I• • n '••• 1. 70.kl Ad.lts
120 85 50
102
n
43
CHAPIH 15
AGE ANO Vv'EIGHI
2.,
111t'1l Ill,' ('\('11 g:n 'ilIN than llo!t'(1 in Tab lt· I.'}-.·l Thus. add(>(! atte ntion lIlig:hl h(' wn'n 10 n "t!Ilt.'ing: Illaillh 'mlll{"t· do~aw' in t·ldt·rly \\UIIlt' 1l and Increasing dosagt' in )'Hung 11\('11 . Dm ag;t' ill olll,'M' and t'lIIild ah "t1 patients must also hI' adjusted to ma int ain 11ll' sanu an'raw' IInlll, llInti ph\lIIil o uuvru mnon. Usua lly. d nJg:di min at ion (t'.g:.• re na l clearance) is lIot illl,,"t',l"It>(IIII,'t'iIllM' o f add{'(! ad i po~>(" tissue. All exception may Ix' in t1 n lg:s \Imlt'fg:Hing: g:llI{'n runid atioll, ill whidl l'il-....· rln-re is an inen·il-....• wi th nlx·sit)'. People wi th lar-,;:t·r body lrunu-s (Il('ig:l.t and luuld} prohahly ha\'t' h i~lt'r clearan ces. T o a first apprm illliitinn (h,l"'t'(! 0 11 IlI'ig:ht alo!lt·) ~tld l illl·Wa.....·S ran Ill,' t's tilllitlt>(1from Idnll lJ( /(ly It.'dJ!,ld . kk-ul htll,ly wdg:ht in kilng:rams (fr om lift, insurance actuarial stud it'S) ca n he eslimalt'tl From the following: r{ · b tion~hi ps \\i th I Il,M I~' Ilt'ig:ht.
Ideol body weight lmenl = 50 ... 0.9 1 (height in em - 1521 Ideal body weight lwomenl
=
45 + 0.9 1 lheighl in em - 1521
T Ilt' 1'\ 1)(>('11'(1d t·:lr.lIlt'(· of t-n-atiniue can t111'n lit' calculated Irom Eqs . I and 2 for ad ults. Fo r t' IlMda h'(l pal it'nts, estnnat ton of dosa!!:t· n 'fl" in 'Illt'UISis ev t-n mo re compk-x. Dos 011-:. ' n-quin-nu-ut s dqx'nd ou lilt' t'ill\\(' of III(' emaciation. ~t al nnll ri s h nlt'n t am l va rious t1iWil<;t· stun-s lIlay alTt -c·1 n-nal and Ilt'pillic elnulnation. In most of slld l palit'nts, howr-vr-r, dnsag:l' rt 'l l lli n 'Il\( 'IlI ~ an ' uot (,(IIllIllt'nSl.ratt'ly reduo-d with IMMI)' \\·t'i~h t . Jdt 'aII MII,!y Wt'ig:h t may tln-n Ill,' a Ix,ltt'r app roximat ion u f unbound ch-a runce andmaiun-nancc d( r.o;in~ rate. C lt'a dy , umn- dd ini li\l' Iufonuatkm is 1ll'('tlt'(l for both nlx ·S(· and emuciated palit·n ts.
Neonate TIlt' lark of maturation o f renal am! he palic funct ton m ccssltates thai tilt' ran- of udnuui\l raliu ll of d Olf.:s to IMlth neonates an d yu ung: infants he Tl'(IUl'l,(1. cwn 0 11 iI hody wt'i~hl l"lSis, if to\(itil)" i ~ to Ix' avoided. Unfol1l1nal d y, dJan ~.'S occur so rapidly ill tlu-se t'arl~' sta1-:t's of lift· Ihal il is imfMM iblt· to pn'tlid \\i th l'(mfidelll'(-' clearance and hence tilt' n - qnt red dOsagl' rt,,.,rinlt'n. Cauti on mus t dt'arly Ix' exerci sed in adm i ll i sh' ri ll~ drugs In this 1"'lit'1I1 IXlpublion . Ut'sitlt's l'a n ·fully not ing: n'spon~. II1nllil(l rin ~ o f tilt' p lasm a ('(II\('('Utrutiou of dnlg5 with a narrow therapeutic lndex should 1)(· helpful. In passi ug. 1I0It'\\ '0I1hy ln-n- is the intidt'nlal t'xp'lSun ' of h-tus and slll"kling; Infant 10 d Olg:\ . For Iho'O(' d Olg:s Ihat ( ".1Il 1l:I-SS till' pla(,(,llla . Ihe unbound plalt"lll concentr ation in tlu' fl"lus is likt'ly to eq ua l that in ti lt' p n 'g:lIa nt mo llll' r in ch rome therapy. W Ht. dimi nati n.l!: (':ll);lt'i~' g{'Il('m ll)' l)fll,lfly t1t·\l.,lolx'(l. Ihe fet us ac ts for tlu- most 1l:111 as an addilional - lisslleof t1istrihulion . \\i th half-life in tln- fet us IX'ing: the same as th ai ill till' mot her. :\ drastic d .'llI ~t· {M.'('1Ir'S, hm\ 't"\'('r, on t1t·li\l' ry . Dt·pri\l.'(! of alU'SS to tilt' fully dt,,\·(,lolx '(! dimi naling: orga ns of lilt' motllt'r, {·lim inaliull o f dOl!!: frolll Ihe Ilt,\\'!)fJnl dlild m n Ix' w ry slow indt'('(1. 11It, slll,k!ing infan l is t'Xllt ISl'(1 to th ost· d m g.s takl:"n hy th e IIml llt'f. As sUl·kling: Ol1:lIr'S rl'~lIla rly. uf { 'U II{'f ' m art ' .'\ l 'nh ..I pialellll. 111t' ri.de' an' ~rt>ah'st for d nl ~s . pal1il'lIlarly Hpophilil' OUI'S. thai l'(IT1('('ntmll' ill hn "I-\t milk. thai an ' poorly d ('aft'(l by tilt' infali t. illill that ha\"(' t'litit- index.
111t' ('vit!{'Il('(' in Fig:s. lS.....'3 and 15-1 1 SII~I'S tS IlJilt a mainlt'llanl'(' R~ n1t'n . m lclllalt'( l hy (,(lm't1illg: tilt' ad ull dOSilge for Ixxly \\'('i~h l , m m ld pn )\'{'inad('(paale for childn'll . Mpt'tially for tilt' wry Yll1l1lg:. IXJSiI!?:t' R'(llIin ·nlt'llts. l'ilrtlia<.· oUlp ut, Ilt'patic and n 'nal h!{)fxl flow, ant! .~ IOl llt· m 1a r riltmtioll mil' in d lild n'u and in you n~ ad ults of \\i ddy dilTl'ri ll ~ si7.t·s haw Ix't'n found 10 t'(,m·tatl' hd lt'r \\i th IJ( /(Iy .\ ,(' 1"(I ("t' (1 " (/ th an IXlIl)"wl·i ~h t. Bt't'illlst· d t·ard.Il('(· rl·b lt·s t1llSill.l!: mi l' 10 plall'a u pJ.tsma (,(IIlt'('lItmticlIl am ! lx't~AUst· w llal dt'a nlll('(' is pmlx ,r-
,.,
C HAf'T £ ~
IS
Valproic Acid
Carbamazepine
0.8
3 2.5
0.6
2 0.4
1.5 1
0.2
0.5
o
6-12
o
1&-48
13-1 5
2-7
8-1 1 12-15 16-20 Phenobarbital
Ethosuximide
10 2.5
7.5
2 5
2.5
0.5
o
o
2-7 6-11 12-1 51 6-20
<2
2-7 8-11 12-15 >15
Age Group (years)
""'It.. "
nil:. 1.5--1 1. n M' r l;<>m" d rul( <~ ""~", I h,,... " f .......no! "''' 11<,,,1., '11' -,In ,1t' "' " ..•.., ,, ,,.. 1",fl" r d, n.uic.. oJ ""..Iit·..li< .. in . ....ilo.l An !1ll....,... ..J d ",}('I" r"" ~llr ~.. m ,,( lu ly "" "10:1'1 1'1041" . tI ..• 10"........li" "I" (...........,lr..lk.., In .W~ .10: J-" 1dlo w ol'" in ,",' )' MlI1",...t d ,;I.In-n. IA,Lapl...1 Imm II..• .1..1.. ..f ~l "rwlli . ".I A: l"k' .Imt'_I" Urut, l>i' P'''';li'''' Dllring 1>' ''' '\''111111'111, ~:'I1" ..I I~ 1' 1. \I" ",,·IIi, s."", '·<>r~ . SI"'(1n"" rt ,hlit-..t ic" ... 11:1';"';', CI...., II . 1'1' J I I-.1hlI.) fI..
. ."Ii.,....
tloual to ~IOI llt'n11ltr fil tration run - (St"t.· Fi~. 13-11 l. the <:hoi<,-' uf sunat'l' an-a owr w(' i ~h l a.~ tilt.' IlH.'thud o f (~.tk·lI lal i ll~ maiutenancetlu-ra py 1Ia.\ SOliI(' j ustificat ioll. Takill ~ II ,5 5'yl'ar· old as the typkal patient n"(-'l 'i\iIlR till' dm ~. the dt"lImllt'l' expc.'l1t'(! for a 7()-k ~, 20->t'ar olt! is 1.4 tunes that for till' reference p atient (Ell_2 ). Al'l:()nlin~ to this concept ,I d lild's maintenance dOS;I~t' is calculated [mm the fonullla :
Child' ~ maintenance dosoge
• 14. '
[
s' rnxe cm2 rec 01
)
1.8 m2
. Typical adult maintenance dosoge
4
when- US 111 2 L\ tilt' surface an-a of an a\/t'm~t" 7()-k~ ad ult. 111l' surfan ' an 'a of a clnhl can
243
CHAPTH 1.5
Ill,' ddc'Tlllitwd [n uu its hClI,ly \\"(' i ~ll tusi ll~ the OI)S('I"\Ollio ll th at surface urea is p rop ort ional 10 I M lC. I~' \\"( 'i ~ht til tilt' II., IMI\\"('r ( wt'i ~h t n.). Us ill~ this Llst n-lanonslnp. Eft. .. may ht· n-wri ttr-u as W eight of Child] 0 7 Child's _ 14 . [ ma intenance dosage ·
(kgl 70 kg
• Typical cdclt ma intena nce dosage
5
To illustra!c' till' lI SC' of tilt, n-lutionship t'.\ p rt'sst'tl ill Eq. .s. (:onsidt' r ti lt' example of tilt' anti hiolil' t o h ra l1l~ 'C.·i ll : tlu- usual adult tnaintt-nnmx- dCN' is 3IIlWkv: clail)' P\'(' IJ in th ree d i\iclc'tl clost's. QlIt'stio l1: \\1m! is th e daily tC)hm lll~·'C.'i 1l dosa v;c.' 1iC't'tlt'tl in a 15-kv: d lilcl? :\l1s\\"('r: 1lI0 1Il~ c1aik Th is ,lIls" "t'r 1~..11\ I...., c's timalt'tl Irom the mtio of surface areas Ies timale'tl fWIIl IM~ly w"t:i~ll t ) lISill~ E/). 5. 15 )0 7 Child's dcsoqe of lobromycin ., 1..4 x ( 70 . 70 kg x 3 mg/kg • 100 mg/ doy
:\ol k t· that the- wt'i J.tl l l - llon ll a1i "~'t 1 dail)' c1c}S(' of tol mull)'d n ill till' child . 6., mW1v:. is nun-h luglu-r than tltat in tilt' aclult, TlIC' n-ason is tha t cleanuux- is proportionaltu sm fan ' un-a ami sur fuo- an-u pt·r l.i lcl)?;r.II11
;lIcn'fl.\C' \
clisp m pu rtion ate'l)' with dC'('n'asill~ \\'('iV;ht.
Tln- nc't'C 1 for a hiv;llt' r Tllainlc'Il,\Il('(' d(}S(· pC'r kilc'1--rr.un lxx ly w"t'iv;llt. ti lt' smalh-r an d hr-nce usuall y tlu- )ll ll1lV;t'r the- c·h ilcl, is sc't'n in FiV;. 15--3 for chtldn-n hd w'C."t'n 6 mouths and 12 yc'ars. :'1:011 ' tilt' l11111p lt' IIlC'utal'7-' c1t'1:rt':lSt' in tilt' llalf· lift' wtth dC'('rl':Lsin ~ size.' alltl a~(' . Thus. no t oul y Illay a l -~'('ar-ol cl ehihl n-quin- a I:lrv;t' r matnn-nance c11}S(' pc'r kilc'h'T:un I x x l~· wt'i~hl than an adult. hut ht "t.~IllSt, of a shnrtN hal f-lif(" till' d rug lIlay also need to hc' p\l'n monfrc"l l' lc'utly. T his is c'slx"t.' ially so if the dOl!?: h ,l~ a low therapeutic index am llafj?;(· 1I11l1uatitJlls am llllCl lh c' :1\·t' r.i~C' plateau ('()IJ('('lJ!r.ifinn an- tn ht, :l\uidt"tl.
The Elder The d elt·r1y ('(ms!illl lC' an i ll (' rt·:~,iliJ.tI~· gn-un-r p mpn rtinn nf th e total pnpulati uu .l1lt')' ,JSt) ('(lIiSUIllt' mort ' pn-scription dm).,~ I....-r cupitu tha n do pt."llplt' af any orlu-r a~{' . As a hm;l(! V;t'Ilt'r.cl i "~llinu . c1C1S:I~t· sllCllIlcl llI,' n-duced ill dclc'rly pa tk -ut s. rt'f1t"t1 inv; the ~t'Il('r.tl c1t"t.·linc' ill Ixxly lum-tion witll a~c' ( F i~. I,H). A reduction in dOs.;I~C' is 1Il"t'tlc'C l pa rtie'u lar ly in tilt' weuk am i in firm c ·lclc 'rl~' !l:ltit·lIl. Such a pali t'II1 oftc'n su!Tc'rs [nun a -vr-rul dist,it-St's. n-celves multiple c1rtl~ lIlt' r.IP)'. ,mcl h ,~s Ixxly Functions tha t ha\l' dt'(,rt',LSt"t1sharply with acl\":Ull'i n ~ vears .
( :('rt ainl y. tllc' IIlarkt'tl mlc l pn ~rt's si\'l' dc'C,rt"lS(' in n -nul funct ion illlplit·s tha i tln- c lns:t~t' ft'h';nwHs of clrtll:S that an- p n 'tlo millan tly ex("rt,tc"tlllll ("han~t'Cl should I...., ft,lul'C't1 in tilt' t·ldt'rly populalio n. For c'x:lIllplt', an .';()-)t'a r-old pa lit'nt n-quln-s. on an 'mv;e , cml)· ,()Ik of thr- 1I' ual ad ult cln,<:ll-:c' C'\prc'sst'Cl rt'lat i\l' to ,() kg of Ixx!y weiv;ht. The c1c}S(' n' luin>tlma)' Ill,' C"'PH It,SS I x"t~ lll st' tilt' elclc'r1y p atient is, un a\l'ra~c' , l i ~h IN , A dt'p rt's.St'C 1 dc ·ar.cn('(' \\i thnu! clust· ,uljm lnll'll l pmhahl y t'xp lains, in Il:Irt, tilt' in('n ':l'it"t! fn"tlut'lIl'y and c1t-gn 't· o f adw rst' clm~ t'!T("t.·!s oltl'lI no!c"t! in ddN ly pat it'llts.
General Equation Tel rd um 10 tile' ('\am plc' of ('n'al illim ' autl similarly hanellc"tl c1mv;s, fmlll I )l'ar to 2U)t ':trs of a~c ', tllC' rc·la!innship Ix'lwc"t'1l n 'nal dt':U,\lll't' allC l ll~t· is c"pn'ssc"tl in E(l. 5 : IM')'tlllcl211
CHAPTE R 15
)l.·al'li, this rl'1alionslJip is expn's'>t"tl in Eels. 1 aml.'i Bt'<wN'I!lI' vulur- of I ·Ul-A ~t· (hlll~t ·s Iilt lt· IM.·lwt"t·1I I antl2n ) t',11'li of a~t·. these - t~ lllati(Jll s (..Ill 1M.' combim-d to ¢\l' tilt' ~t' l l('m l t"tl" atiu n:
Ma intena nce
do""",
[140 - Age (yea rs)] . [We ight Ikglf)7 U5l.~1 a dult 1660 . ma intena nce dosage
6
thai !:M.·nnih IIII' nJ1l~h appru\illlalioll of ,LlIIaill!t"Il;lIIU ' tlo"L~t · Il ll' .1 1l.tli' ·lLl lIf all)' ;I!-:I', tilt' Infant amll ht· neouate-, wln-u mainlell;ln et· of tilt' Sitll W an 'm!-:t' unlM. lu llIl plah';111 conceutration i.s needed. :"0 chsn nction in ~(' IlI IN n 'fjllin 'lIlt'lIls is madt,. Tlu- \, IIUt, (If lilt' tlt 'numinatu r, )661:1, in Ell. 6 is lilt' pmtlud uf lilt' a~t'-rt'lah"tl ",'(·Iim' ill n-nul ck -arance for a ,'j.S.yt·ar-old: SoS ( l oin - ,'j.S) an d iti )';' or IU.5. Fi ~m' 15-12 suuunanzes tl.t· dOSit~I' dtilll~l'S with a~t· hl')lJlld ) )l 'ar n-qutred tu mainlain tilt' Sim I(' a\"(·r'.t~t· nnl M.lIl11d (1)lt('t'lIl mlioll. Tln- nuunn-uaucc dosin~ run- Increases ulmost lilwarly between I and 12 )1.·al'li of agp . 111t'S(, pn"tlit1ions a n - bused on dmll ~I 's in hotly surfao- an-a .... tth a~I' . which art ' I'slimah "tl fnull a \, ·r.t!-:t· w, ·i~ll t S , alltll 11l' ~t'" Nal correlation (Ib~'n.·t'l IIM. ,"\"("t·1l dt·ar,II1I"t· al)(l l)(M.I) slIrfaet · an-a in childre-n. I\I"(';IIIM' clearalll't' tncn-ases up ttl 20 ) t'i1rs (If a~l' alld tllt' ll dt'(·lil\t·s tln-reafter , then- ;Irt· pairs of a~t' values for whit-Ii tilt' satm- rate of adllli llislnllion is n-qui n-d. Fur examph-, U ll a\'(·r.tj,(t', a 4 '~1·ar.ultl chik l (16 k~) n'i l' li rl'~ til(' S;t lll!' rate tlf drug ..dmillisl ntl itJIl a.~ a UO')l ·.lr-tllti IWJ'S(m (60 k~)_ Similarly, iI 12-yt'ar-ul d d lild (:39 k~ ) rt'illli rt '~ lilt' SaJllI ' daily doS(' us tlnn -fen-nce iO-k~ lliltit'ul. naull' I)', tilt' usual majnn-nam-e
A
1.4
B
~
;; ~
;; a: 0
'" 0
':g 0
~
':g ~
0
~ ~ ~
1.2
~
1.0
~
~
~
~
.i!!. :i''5"
'" -a
0.8 0.6
~ ~
=>
0.4 12
4
6
8 10 12 14 16 18 0
10 20 30 40 50 60 70 80 90
Age (years) .·IK_ IS-1 2. \"~ri,dio,," ill II,,· mai ,,"''''''''~· ,I" , ml: rat.. ....pn.....~ I .., a fr...1"M' ,,r II,,· m.•iIl1 ,·, ~n " . · ,~"i n~ rdl, · in Jilluh (.Iut" "! Il·rtir.-..l lil,,'1..' ~ flllll1io.N. nf ~ ' . (nnll 1 W.tl" 1,, !J1\I'm . -' uti' liN' ..InN'" IUN';a)" iI K"" ~"" in "..unk""'K~· ,~ "i"l: 1'.. 11' " i ll...",· fm", I ,,, 12 ~1'''''' l. ;I,' ·.1.II'~ l l'ri,,''''ri~· " i ll, ..n ;110...· ;1,...• in 1..1:U/~', .. ,,,l lh.. ..rn,,'" lin..... ' ~"t1i".· 1.""" '11 .10 ..,.. I \JU ~";'I' au. a' ;;oI.. II' ri' n..ri l~· ",11, ,lillli "hl,, ~ 1 "n,:;o" (" ••1io N' ",11, . t.",.;nj( " ' ;0... . .",1.., 'IO N" II..., tl. · ,~"i"l: It ....';o f", 1io." ..f "1:" ,IiIT,-r 10·.. I. ' "••n· II"", ..I• • ,t 2.5,f,>Ic1 {nolll 110.· "" ...1~ I"lt , ~ "i lll: r..I<' . \ ·.. 1,.... ..n' .".1 ,1..1<.1" ,i " l: ":'1 f> ..,,,I Ih,' "'''I:I,;.f"•.~...· n·I<.IIio",.I" I" gi\1'11 in '-;11. 1 ~2. ~ ~"'\1'Ar-4lk l
t."'
CHAPrE ~
AGE AND 'M:lGH1
15
2"
IISII,II adult dosa~l' is \mrtllwhile wln-n adm inistt'ri ng d r ugs to the n-ry}UlI lIg, to t he (-luld. alld 10 rlu- agel!. :\ correct ion is also worthwhile m cmeciated and ohe S(' patie nts. :\ fina l no ll' is ill onb-r \\;111 reg ard 10 changes in phrsi{)l~c pa r.Ulll't ers co ncermng a~l' . Phys iolo¢ e parameters such us cardiac Olltp ut , hepatic blood blow, renal blood How. a lld ~lo rne: ' OI l a r filtmti(lIl mi t' c:!e:"<.'rt"Lst.' with a~e ( FiR, 15-4 ). 11\(' values mos t \\idely quot ed, e: ' .~. , ~lnl1ll' OIlar filtmlillll rate = 120 mlJmin, and hepati c blood How = 1.3.'5 L'nun. art' t~Vieill fo r ~u" ng Iwahh)" ad ults, uot 1111' typical patien t wh o may If{' 5.'i o r 70 )'l'ars of aRt'. \\1 Wllt,\'l'f compari sons a rt' made in l)l)il~d.! pa ti('lIls lilt,)" should 1)(' d une c..m 'fully. For t'XiUllplt' , a n Ilt'pal il' bloe:xl clea rance o f 0.7 I1min fo r a drug may indicate hiWI Ilt'pal ic extraction in a 70-year-old pancut po pulatio n ill whom the hepatic hloe:xl flow lIIay If{' 0.8 L'mtn inslc:'ad (If 1.3.'> I1min . Simil arly, a renal d e a mnt1.1 fu of 70 mllmin 1I1i1) ' 1)(, e:'li llitl 10 til(' GFH of an t'ldt 'r1y patien t po pulation .
STUDY PROBllMS IAnswers 10 Study Problems ore in Appendix 11.1
I. Comment o n wl l('t1lt'r pach o f th e fo llC:J\\i ng statements is true or false. Qu,t1if)' )uur answer whe n )u " tbtnk it appropriate. u. O ral hio:l\"ililahi lit)· increases \\i lh i nl'n'a.~i llg Ixxly \\"t' ight. h. \'ul lln l(' of c:Iistri lmtio n va ries in di rt"<.1 p roportion 10 hod)' wt'i~h l , e. In cluldn-n. dt'
T.bl. 1 5-4. Aw._•• D. . . ._phl• • 1HII ............IcI.etI. IkIta ,_ Dlph••h.,... ,..r..8Q 32 Q3
~ lyeoJJ
We
Cleorooce IVII'1
Volume 01 d '~II 'bJc: lO'l III
~~ood"""'~, ~ J .. odooIy~
32
70
Q8 1223
6QO
W
...
"""'1/_
._lJ, Il..e.~C atd!-ono,fE J ~ 30665-671 .1 990
co"
'
6Q
71 50 Q66
~ Pto••,..<.,1"..... o atd~
a. Arc:' t he:' dilTI·rt'n l't's in volume of d istri butioll ac ross th e aRt' ~n lU ps Ihc:lS(' t'xpt'(1t'tl ? h. Art' lilt' c:litT('n' un,'s ill clearance acros s lilt, age gro u ps those t'xpt"<.1ec:..l? 3. 111e:' us ua l adult dosa g(, regr rm-n of a drug is 20 mg once a day, \\11al darly dose would )l JU n-conum-nd fnr a 3-) l 'a r-n ld . IO-kg dl ild ? ~ , Cakll la!t, a mai n!t'uam:t' c:Ios.agt' rt'Wlllell of geutan ud n 10 treat a seven- infection t',IIIS1'l1by r.~ I·"dOlllmw.~ tl/ ' m gillOsa wi th tln- o bje:"<.1in· of ma.inta.ining tile:' salli e a\1.'mg('
coucent rution in : a . A cluld. OI1-:t' ~ ~'t'a rs , \wight 15 kg, wit h normal renal Iuncttou fo r its age.
AGE
246
20
E
• • • • • • • • • • • • • •
15
;;
~
c
E 10 '" E~
u 0
e
.., ~
•• •
••
5
'i
'-'
•
f#)
O W TE 91 5
W'EIGHT
• •
•
•
• • .' .... .e.,.. .. .,.. . '1-· ·• .-. .:• •
• • •••
•
•••••
•••
•
o -0
9 days 5 months 2 years 6.5 years 16 years 33 years 61years 104 years Age
t'I". 1.5- 13. C"·Mr..,.. ~· ..( ('<·(trY,I..,.,,' III.,, 1.;''('(1 frulll I tl..~ tll !:t2 ~" ;lO ..r ~'. t:.-h .~ tll l • .1 "1m ...·Ilt- .. \ ;01",iU;ln illoli"iol".J . S uI<' tlo.- ,,-.do:. ru, "" hio:b i!. 4,'" r..; ....I,.. thr p""" ' r ,,( UZ,> ( :o.~." rll. ( ",.. 1. ;1\0,11 (rulll " ~ t' " '. W_ I ~ ;",,1St,n-l<..1. " ., :\~;&'''' ''-iat I .-h.ut~-S i ll n ·ftri;lu....· I" ';tm ' tr........., C:Ii" . 11"," " ...ol.;,.. 1 .• 11,7n -M , I!M 1I.1 1n.1"....1wilh 1,,·nniI.UOIII Ur .\ DIS P........... ".trk . la J't:-' U mit 1.)
ebk-rly f"ul
Hlil'?
6. Blydwrt l.'I al. stud it'(l til(" phan llill.,(lkilld i('SHf the- ('"d l d ll lll illlla j,(ollht ft·llld ip illto, IlSl"(1 in ti ll' lIIilllil"l'lIwnl of h)l'll'I1t'n siHII, in a ""IIIP of 14f) slIbjt '(·ts . All suhjt '('Is n'('('iw"(( I·it hl ·f 5 or 10 1II ~ om lly twi ce- Ib ily f OT fi 10 30 days. Fortv-t w n of 1(.1'11\ also n '('('i\"("(1 tilt' d nl~ inl nl\l 'Unllsly (eitln-r 1I.c~ IIr I .S Tn,,:). Tl n- suhjl'(1s wen- IIhi dl '(l into tlm'(' a" t' ,," mps: 20 10 3 H }l·a rs . .In 10 5~J )l·ars. nne] fiO 10 Ml }l'ars. Tahh- IS-.....'5 sunuua ri..~ 'S till' d(' lJIl~mp"i l' tliia am i p!l;tml'\(''Okilll"lit' fiIUlillj.(S. Ch-a r a~('
AGE
AN[)
'NElGHT
2.7
M_.. De • .,_pkl. D.-. _IHI •••M.pl•• "'- 1_S-,. ......... ,-_..ten _IHI M __,.,-
,_
"" ,""" 2~ 3Q 4~5Q
60-80
""". 70 30 40
"'~"""'''''''''8Iv<_ t Jl 1~]4 lQ\ll "A!.C
,"
""
"~,
......
.a"",
"
26
76
52
88
17 12
68
77
13
,_, ,..., 0
"" ...... I
A~
.......
..,....
...
0 82 0 64 0 45
24
Q
DOS!
~
....
'OIl
"
2Q
~ -. ~ ~
" ' " OO>NG .l,(,.CM 10-12101"
.",'"
0.Q28 0 041 0 052
a J CJ,n ~01
'*'"' to....'''''"..,,, ID-<j "'''' .
III ,iIIswI ' ri n ~ IIIl" IIUI'shullS below, tln- cleunmcc values t"Stimaft'1! from till' t.v. Illta ill lilt' Ilm 't' su l~n m ps ap ply In all lhoS(' in r-ach of lilt' n -spcctlve ill!:t' WOUp". a, \\'illl ad hity rt'sid ill!!: in rlu- IMrt'lll lim!!:. comment Oil tilt' 1lt'1'11 10 adjusl rlu- doS(' o f fl·lollipilll· for a,e;t', h. CUlIlIIIl'I1t 1111 wlw lht'r till' d istrihutiull of fd ollupim' vum-s wil l. a,e;l', e. Eslim
">'!MGt 1I:"" 0 0l' WEIGH! TOOfAl. llCO'f WE01lI'\l
29 981
27 937
2Q2
91
032 107 281
0.47
143 153
165 16 2 164
91
98 95
\\1mt t"plains till' t1i fTt'n ' nn ' in IIlt't'fTt"'l't of ol)("Sity on 1111' volunn- of di st ributioll lilT ('(It'll Ilf tlu- clm,e;s? h . Wlt at illljl;\C't tin suc h fimli n,e;s 1m\'(' 1111 lhl' dl),>;l,e;t, rt'hrinll'IIS uf these t1 mh>"S'~
16
~
DISEASE
OB JlCTlVIS The leader win beable 10: I list a! leasr Sill deecses in which the phom'oOCokine41O 01 drug~ is knQlNTl to be cbe-ed 2. usr and brieRy discuss the phorrnoc:okineric pOfOmetefs rhol ore chen cseed inpotlefllS With hepatic and renal disea!l8S.
3, Judge, using phormocokineliC principles, on when oltefOlion of drug odrmntsncnoe should be cOMidered 101 patients with becotc Of renal d'secses . 4 , Estimate !he creatinine clearance of a patient hom
the pcneors age.
weight,
gender, and
serum creonntre.
5. Esrimote how much the clearance of a drug of known froc.tion eltcreted unchanged is deoecsed in 0 PJ1ient With known renal functton.
6 . Eslobli!>h, from phormocokinehC principles. a dosoge regimen !Of the pot,ent in objecrive S. OrTlQUfll in ee body with lime loIlowing the do$oge 'egimen fecommended in objeo"", 6 . 8 . list the O$$UmplIOflS thor undEKlie the application 01 renol h..nchon rests in d<»oge regimen odjU$lmenI for patients with renal insufficiency
7 . Sketch /he
l>iSl· a.<;t· is a major source- of \~d.riahilily in dmj,t rt:'sp, mM·. For lIlan y (LM"a."t.'S thi s \1lriahility is tim ' primarily 10 d ilTt'n'III'C's ill pharmacokineti cs , tilt" an -a uf prillt'iral Focus in this chapter. " It' chapter hegi nli with a ~t'Ilt' rdl di M.1ISsiull o f t IiSl'iL<;l'S known 10 arret_'t dnl~ killt'til'S anti l'Olld \l{lt'S " i ll. t'rt(' nsi\'(' rh-tatls 0 11 atljll ~till ~ t1n1 ~ :l( llTIini ~tr".Il i()n in patients
wnh renal in sllffidell l ')',
DISEASE STATES The pharmacokinetics, a.~ we ll as th l • pharnl;l('Od~,mlll i('S . of SOIl1(' t1n1~S has la -en s llm\ ' 1 10 1)(· illlhll'lIn't1 hy tht, pn>Sl-'lIl't' of concurrent diseases othe r than till' O lll' fur wlnch a drug is IIst·.1 Examples o f co ncu rrent diseases that illl' n ·ll...• vart..hility ill dnl~ rt'spoll Sl' are ltsted ill T ahlt, 16- 1. 111t' subsequent dtscussjon centers on Iht' first tlmO(' ~n )lIps o f t1i<;l'IL<;l' listed, mlllwly !Jt·Ilv;loblllin, 11-"''''11 in IMlIlt' marrow trunspl ant p auents for Ihl' prevention o f cyt omcgalcvtrus ccmphcanons. In lh l'S(· Il
..
,
CHAPTI P 16
..
,
1)5£""
..
6--,. . . . .pl.... IneNaNtl Va,....lIlty I. Dr.••••pe.... Auecl..... wi'" c._.~ DI. . ._ S.....
Taltl••
V ~tCNN
C<;lI\OI IC:l'<
eeoc
~·co.>eO"" "-"",~ c."~l
-"
I\c..-e .. rot
W"rb,n
Ca"~
todoc",ne
=d~
C>SS
Q65EVoi"'tCN
"''0
'"""""',....
Sb.o..-IaI irl pkw.o
•
'"-"
000
"* .-.atIOl1
.,..
AA!>O'¥m"
COiOti"""""ak.
G
dnt>boo/lC
~~.
Th_ " "'""'"'"
Gd,"",~""" na d '""'''''' C.~
d,_ C, .,t,nl .~.
-FoMJOC cod
' ''>pm""" d ""~""l
"""1::0::.....001 "9"'"
"'x'"
hc>t!o>ed 1Ol
.....
_ .... -<-..... "'"
roeo-l sensilivlly
C>",<
Doc lo.-oc,l,n
Io.uen ,,"" cllO>
•
Penal cleo
(),go,,"
""boo<
Bronch;,d,laO'
.,..
Cor d >OOC!l ""
,~
Qv, n,....,
'edo::"
doI.dgt 10 ~ ,,'" oIlO>.o<:,1y
•
Pe<:ko do>e 10<MlKl e>'e !Joop.ng lime
Booo-o,labMv'no;,1IOlolld ond/(J// dl!l(JIIO"ICe
..........
d,m j",~
NS
"'bor.::l,"9.
eIoMJle,d
lI ,·
-----
oc.d~~n
-~ onIv In. 0Cfr>0e
...
•
CCII\OIO-=-oOtl
d.--.",
kT>"'Ola''d1 "9""
• ....t.i,,Noej ""'"". 01 ,.".ooboI~, - ""~".." "",«>" ..., "",.......d doe to d ......
NS ~..,.,
d,,.rbuban "'""nlol>ecl.
~
IW>rph,ne
n.,.""
C""'onc" o.-.l...oLrn. 01
~
,.""'"""
t"'d<X' ......
PecL:e dcoage 10 leo.-.
'ed.o:e dosogt 10
--.....
M:xe
-
•
./-
Toll:o.r1Om";" Hwogfve""''' "9""
~,~
~IO><'C'''Y
,,""01hemorrhage
................ ,........... • ....---. ""' ....... • ,........... ....
"'"'~
!,bl
CQMWN'S
Cleoto<>ce ,ed....::~ , ,..due" do>oge 10
""" .......
Pe"'<J: 'h '''''''' GenIOmO<:ln
""""'" •
,~
....... " """"""' ,...........
""""",0
'
h I;.""
~~.
"""""'0
NS
N'
~'"
~educet dose 10d,ml"''''
,,"" 01 ""P'fO'OtY
""""""' ........ "
Reduced(J//........
•
•... ceec-ce
,...........
•
~o;
-----
•
AdjU$l do»oge <XC<JI/d'''9 10Ihyfood OC!'''''''
N'
!Mpa"ed fhelOboI'vn
""'-' ....... ...,.....
Ovg eIe.oed.
d_
-.... ..............
,educ"
dc»e 10 \e$wll~ rJ 10><0<:'''''
[),,,,,,,,lh«I~ ",~,m;
....... ~cJ
dearance
oeoeosed.
•
~,
rna,.--:l
10 'ed.o:edo::-> ,n
_ " lob ,1or loI<JIM
25.
CHAP1£R 16
Hepalk Disorders Ik(~Ul Sf.· thl' [iver is the- major sill' for d nJ~ lIll'tilho!iSIlI. all imp res sion p n '\ "ltils thai special care slulIIlti ht' tal('11 ill atllllinistt'fin~ drugs to !);.llit' lIls v.i lh di M'iL\(' stat es lI K )(li f)i n ~ Iw1'I
ill t'Clll flid . (}IIt·
n-usou fur rlu- ('(mllk-! arist·s Irnm an attl'mpt to d 'l..s i~\' lwpatic-di ..o nk-rs lL'
II
sillJ'lt'
entitv. II tJ\\ '('\ 'N . disonlt'rs of tilt' her-r. It ll..11 or d ifTlIS(' , an' caused bv manv di st ' il'i(' S; each diS('"~W afTed s various ]('\"t,I, o f Iwpa ti(' ory!;ani7.dtioll to a diffcn-nt ('x·!t·nl. '\'ilh few l'Xl'('Il-
lion s, tln- bepatic- clearance o f d n lJ!;s is, O il a\"l·t;l~(· . d('{· n:·a.~'t l in ci rrhosis. III contrast, in at'uft ' virul ln-patttts. Iht'n:' appt'ars to be a f.url~' (...-en tlhision h('lwet'lI Iho~' d m~ for whid l dearallt't· is rk-cn-ased. or hal f· lift, p mltll l~t'tl , and th uS(' for whkh 110 eha ng:t' is den-en- d. E, is li ll~ data S U~('st tha t dmg: cliuuuanou is tlim iu isht't l in ohstm(1:i\"(' ja ulltlil't·, 11 1t, t·tTt't:1 is t'XI)('t.1:t'tl 10 1)(' mort' t'\h'lISi\"(' for t1mS(' tim"'.... d im ina h 'tl pn:'tllllnillanily hy h ili;u)" excrettou. Anotlu-r potenttal pitfall is to t'fIliait' prul(Jl1~ati(Jn of Imlf·Jife- \\ith t1i miuntion o f ht'!);llic tlm~. nlt't ahol i zi ll~ act ivity. Half-lift' is (:onl",lIt't l hy I)(JII. lola l ck-arano- and volume o f tlb t rilllllio lJ, h\11 lud ep-ndcnt pa rall lt't t'rs (C hap . II ). To a.~st'SS clearance and volunu- o f t1istrillll tion, the- dm ~ sho uld ht: ~ivt'll illt m\·t·mlUsly 10 t'IISUn:' co mph-te bio.a vailahility, \\llt'n "'J stlltlit'tl. lilt' vnlunn-s of d ist ribu tion of some d m g:s remain unal n-n-d in 1lt'1);ltic tliSt·'L<;.t·. hut Ihu~ ' of ot ht·1"'i are incn-ased. An lucn-ase in VUIIlIlIt' o f distnbution is found pa rt k llbrly wi th d r ugs bouud to alhumtn in p attents wit h d rr hus is. Tlu- explanatkm lit's in rlu- dt'pn:'l;S('t1 s}ll tllt'sis of alb um in allt l Ill an~' protetus, ind udi ng: variuu s t' n0 1lWs and dollin~ fa(1:ul"'i , i ll l l lt·~ · p atu-nts . TI ll' n-sultant fall in alhu m in concentrat ion is n-sponsible fnr a dt'f:rt';l'i('tl plastnu h imli ng:, an ;l\ sul1alt'tl increase ill volunn- of distrtlmtkru , and an ;l~ ...- )(:i alt 't l i!l('n',l'>t' in d l'ar.IIIl't' for a t1 nl g o f low extraction. A fall in hepauc t' 1l0 'l1t·s is n-sponsibh-, in la rgt' pa rt , for a duninisln-d ln-panc 1I1l1 )(Jlmd dt'anUll't· tlf IImny dnl ~ . (hitli......d dm~s appt:ar 10 he ilio n ' afTt't.1:t't l th an tlltlSt· t'!im illillt't l hy ("l.lIlj ll~i1ti (JlI . T Ilt' illlllle m "{' of lu-patl c-d i.'>t·'L'>t' o n d m~ ahso rp tion is I)()(lrly understood. 111l' pmhlt'lJl is 1"l.J1llp lim lt'tl h~' li lt' IIt'('(! In <;{'I);lmtt' t1iSI)( lSitinn From al}<;{lrp lioll when allalp·jll~ p l,l..ma (,(l!I('('ntm tioll-linw d ata . It is likt'I)·. thnll ~h . th at tilt' orul h ioavailahility o f tim"'rs lJi ~hly t',tr:\("It't1 hy ti lt' lin 'r is iJwl"t';l<;{'t1 in d rr t.osis , t· .~ . , Fig:. 16- 1. 11lt' rt· art' tv.u n 'S, a l'(lIld itio li ill whit'h a sig:llirit'allt fr.l(1:inTl o f tilt' I)(Jrtal hlt)()( 1 b~l );l'>St·s pa rt'l lt'h~llIal lissllt' in till' livt'r o r t'Illt'1"'i t1in't:tly into tilt· Supt'rio r \"('na (';Iva \ia l'Stlphagt'a l \,tril'(·S. TIll'St· I)(Jrtal ,l\'al sln mls l'all g("('a ll}' illt'n· il'>t· oml biuavllilahility: an illl'n'll<;{' of gn 'atN than :21111~ h;Ls hl't'n rt'I)(lrtt'tl for Slllllt' t1m~s \\ith t·\!t'nsht, first -l);l'>S 1I1(>1;11)( llislII. F m rn th t· furt' goinv; t1iSt'ussiun, il is appa n:'nl tl mt t1m g dUS;I~t' may Jlt't't llo 1)(' ("('1111('('11 ill palit'nls \\i lh ht' I);ltie fum1:ioll in1lMimwIlt il~ a rt'Slllt of 1)(ltlJ d t't' rt';l'it"l.1 dt'amnl'(' ant! im '("('il<;{'(1 oral h iua milahility, All adjll stllll'1l1 ill t1tlSOlgt' is pa rt il'l.Ilarly warranlt'tl w il('li Ihe usu al n 'WI1WIl n:'slllts ill lh t' lI11htll llltl t1 m g l'UlIl'(·utr.t1 iu lI at p);'lt'all apprn'Il-l.i n~ or t'X' l't't '(!illg th t' IIPI)('r lim it of tilt' Illl' m l)('lIlil' l,(lIIw ntmtion \\intlow. This l'(llltiitinll mist,s wllc'l1 Iht' d t'ar.lIIl,(' lIa.<;.( '(1 o n unl )( llInti dnl~ is ,>uhstalliially dt ·p ("('l;<;{'t l. 1)("(,t1N ' it is l h i.~ d t·aroUll't· thai t,(lIltmls Iht' 1l1l1)( lllIIti dm ~ l"l.lIll'(·nlmtitJII OIl pl;llt'all (Sl't' ( ;haps. I I an ti 12). II t'IMtie t1ys fllllt1:ion is a g:rm lt'(l pht'110llWIIUlI . am! Iht'tm 'lit"'llly a t"tl rrt'!al itJl\ should t'\ isl !)('hn't'11dlall ~t·s ill tht· phannal"l.lkindil' I);lr.U1It'h'rs o f dOlg:S, t'SI)("(1,,II)' ht'l);ttit"dt·ar· a1 ll,(', alltl ,Ill appnlpriatt· 1Ilt';L\ Un ' tlf 11t'I);tlie fU lldioll. Atlt'mpts to t's tahl ish SlIl'II n '!atio nsh ips, ,,1t 11U1I~h t'lIl'()ur.t~ng:, h,,\(· nu l 1)("('11 It)(J SIl(1.'(·s.\ful. 111is failurt· prtlhahly ariSl-'s 1)('(."mN'. u nlike d Ol~ t' x('n'lio ll. tht ' f"(> an' llllllWn JilS 1);lth\\"lI~ "S of t1 m g 1llt'lal)( IIi ~ Ill , ('adl \\i th a dHTN t·..t st:1 of ('tJfadur n 'q uin 'mt'nts al u! t'adl alTl't1:t'(! to a di lTN t'ut c!t'g:n't' in
251
OWTEII16
ls-pa ric drsonlc rs. TIll' ccutrtlmhon u( ( 'ile" lliltll\\'a' · to tota l dnJ~ elhninatkm illSiI \1ln ('s with th e d rug. Thls \1lriahilit,· is ilppun'nl (""1l tilt' act ivities of (nuT ht"Jll,tic ('Il7),m's n-. spn nsibll' fo r l,mj ll~lli io n n-acnous ( Fi ~. 16-2). 111t" ( ' II/lUll" activitie-s wen- T1l('ll~lIn'll in )j\'t' r samples ohlaillt'l! h,·hiop \.,·. G lm1Jnlllyltmns(t'r"'\f" app('ars to ))(' unaffecn-d byl n-panc di M'il'it' . Sup port ing this observatio n, till' phannaco ktre-tics of ti lt' ))(·!lIJJtlilUA.· pilll' U\alJ'pam, wh ich is r-ltnnnan-d al mnst t'lllin·ly hy glm.11n1llidalillll. is 1IIlafTr'l1t'll ill Ilt'jla t k d ise;L\C. It is also app;lrt'll t that w hil(' tll(· uct ivitu-s o ( the otla-r th ree l'IlZpnl's arc Oil an·ragt· dccn-ascd. the re an.' sonn- iml h idmtls with normal ;1l·li,i l\" and others in whom \ 1.'T'\. litth11l1h i l) n-nuuus. Alteredmetabolism in chrome persisteut ill'llillili\. dlnlllic .tl1iw Ilt'lliltitis. alll i drrho~is ts llw n '(()n ' a funct ion of tjn- (·1\7.\1nt· in\'nl \"('ll. IIII' slIhs lmlt·. a nd ti lt' aet jvitv n'lIlilining In tjn- indi,idllal palit·n t.
.
.
In drrhosis. a com-Iation 1)('I\\1'(' n tilt' sew n tv of tilt' condition and till ' Iikt'l illOtJtI o ( d-p n -sv -d metabolism by uxida lhl' und su nil' ('~lljugatlf)n reucrious h;ls n (tt'n lx-en reported. In M,\·t·rt' cirrhosis, siWlifit'll by tjn- (,OIllhillatioll of a I(,..\, albumin (less than 3 Wd l ,). au clec a n -d c1()lti n~ u mc (p mth m lllh in umc ~n.·al l· r than 130 11 u ( 1I0nlla1), and till' prt·sl'lIl" of l·Ill't·p ll,,!upat l.il·s. tl m~ metabolrsm is ofh-u t!t'l."n·;L\('l1. Th e
Control
700 ~
400
g~ c
200
c _ ~ ·QE
~
_ cco ·_ ~$E
Q.>
c 0
400 200
1
t·l ·····f
~ 5~ 8. 100
c
~ c 0 <.>
~c
'-" 0 0
Cirrhosis
700
100
······1
······1
40
40
300 200
300 200
100
100
,,~ o.=, 50
50
~H " 'l" '" 1......
T
1
Q.
g a;
o
2
4 Hours
6
B
1
o
2
4 Hours
6
t1K. 16- 1. In
B l~
n " " f'o',.;...."
,,( II. · I''' u l t, • • , ·.d l'll.ti"" ,,( .."U. · I ,lnlK .. f",. '>r.. t ", lrnin;~ n.h"n (t........,..j !inoe) "";Ih 1""'1 ,Ii 1";1;',1...1 , Im l/, ..ft... I,... ",Im; n;""nth,,,, (, 1. , 1hL.--l!i "cl . r"I i "K. ;"'u1l..",.... I. ,"·h· n ni" ..lio:"lu( til<" 1o:1......in n( pn.p,....' " 10...1 , K-'M'lrall< 'm ,Ii ""1 ,,,,1[' n.I'''''' '' ol. '' "fl"r ;4) ", 1",;ni" ,...01;''' ' . CIi'I, 11, "''' n 'lti' '' 3: -4 , 'I-_ 7. Ill" H<1"'. h" II')'· I"·rm i-.. ;,lfl uf .\ Il I<; I'ft"'• .\ u. · Ir.J.a..,J." I,,· U llnh , 1.l
,.1.
~"' AS!
252
CHAPTU! 16
Sulfotransferase
Blucumnyl-
transferase
Acetyl-
Glutathione
transferase
transferase
I
(2.5)
0;.~
20
•
~
~
0
E 15 ~
:!l c
·e
10
~
0
E §. 5
:(
0
•
, ,. ,..•
.'t'•
•
1.2
•
• •
0.8
e
-e:
•
-
,
•
0.4
0
8
8
• •• •
6
•
t l..., ., •
&
'1:
•
6
~•
2
-
A
•
0
•
I
A
4
•
4 c,
~
i
2 0
•
... •
-,•
""
3
n K. 1S-2. Ad i itM-S ur tl..· m nj"lI:alilll: ""~11""S, ~'K, ,",,,~llr..,,\f.·r.N ·. \ " If"lr..,,\ f..r....·. .... '~ ll r. "r'·r.." · ".1 Ir 'r..roL... . in "" n " a1 (hl. "kl ;0".1 ..h"" n n;u (., ole,,) Io""'an I;,." "" ' -;01)' "'llt.·~· . S'",,,,. ,;n"Io ar,,1 lrUl1l1:lo.,. ",r" r 10 h'uf"i 1 wmpIM fnlln p;oh...." ...., 110 d,n",i(' 1"" "";""'" 1"'P"l iti•. dm,nil: ;1(1;\1' h. pat ihs, ..,,0:1 dnt,,,. ;. , ""'1.....1i....ly. n sulr. r "71';': .,.;,.1fn. ;I<'~~l r..."r..r-.......; ,,,"11,,...,,1(',, lp:oTt',..·.4.5..."'ic ..• for II:lub'II'i"'''' Iran, f,·....." ,. I" n ",tr.\..l,,, tI..•"till" ''''~llll'' , Ith""In ",~'Ilr.ul. f,' r~..· d",.. 1M" ;<J'I" 'lll' 1.. 1,,· ;JT' '''1...II~· ",,~· ..f tiM' IM,"'I" · " " "Ll" "". ,~.l... "1'1......101 i. " \; 11,,,,1 1... 1 "f ....1;"; I)o·,,f tI" , k,l llm.., ,' "..,...,,,.. in ' " " ''' I"'Iic'" h . irnl'lie"l ic"" (ur ,1m", l.ri ll"'ril~,.'I; "'ir"'I,..1 hy tlM· t.,"j"It"'ic"' l"'dl....~"an' " .. ·,,1 (A,L.pl ...1fn" ll P..o" lV..t C .M .•" .....I. A . fo'r......·I,L M , Soc" k ri" i. S . T"Inillilli, :\ ., Gi"lw'i. I~ , "-,,,I ( ;;.r,...u. M.: C.M 'j"~ic." p;.>11,.. "~,, in li.... r ' Ii..." ..·. Hr. J,eli ", P1 wn""onL 3f,lA 2';'- -l"l."i. 19'1lJ.l ~"I. l h~ II'"
n,,·
IlIdpt ....!. mn- lIt....-ds to conshk-r if all t'Xtl'lls iH'!\" ll1t'tllIM ,liZt'(1d mJ!; is truly 1It'('(lt'(l or if lUI altemutiw (n 'nally excreted) dm~ is a\
Oreulatory Disorders Circulatory t1isonl. ·rs. wJ.id l illd udt· shock . ma liJ'lIall! h~lx·rtt' llSi()lI . .md lu nJ't'slin ' ('a n liat· failu re, an' "t'lwmlly d lar'1l1t·rii".t....1 by d illlinist.t'(l \·<&-"t:lll"r pt'rfusillll til n nt' Ill' ilion' parts of tln- hod y. Slm1.· hlootillow limy illllm'lIn' d m~ ahMI'lltioll . disiri hutillll, and dilllinillioll . i t is 1101 sll rprisi ll~ thai tilt" pJlanll,l(tlkindks of dm~s llIay 1M.' nln-n.. . 1ill d rt.'u lalury tli'>l lrders . A d iminis llt.... 1 pt'rfusioll of absorption sitt's . t' . ~ .. ~,lslmint t'stillal lr.j(1 and muscle. with all ,lS'>I )(:i"I<'(1 pmtr.u.1t...1 am i . 'rmtlt' dm~ absorption. n-nds to Ill' se-e-n ill pa lit'llls with dt·p n·sSl....l l1lnlin\",l'i(·ular stall's; it lllay 1)(· nt'l't·sSiU')" to ¢ n ' tln- drug inlm\t'llll11sly if a pllllllpt n'SIXlllst· ts t1t'sin'(l. Ilowt·n ·r. ill tln-se t'Ollditilins Iht, kiuetu-s of d istrihllt iull is also arTt"t.1. ... 1. with perfusion In lllallY n~;tlIs dim inisht.... L EX('t'p tiolls an ' tilt' hraiu sud tilt' lIl~ucilnl i lllll . .....luch t1l11St"(llIt'ntly n ....,..ive- an illl'n·'N ...1 fraction of an i.v. holli S dose-, partkHlady ill th(' ('arlit'r monu-nr s. Fur (' ." lIlmll)' ilt1illJ!; alltl t·iln lioa(1i\·t' il~t·lIls . tilt" rate Ilf atllllinistmiioll of a IXllus dust· 10 patients with dn:lllatol) ' d l'pn'ssiull mu st 1)(' 1t'1Il!)(·n...l if till' rtsk o f loxidl)' is to Ill" n ...luced. In tlWst' t1t·pn·sSl...1 d rt'ulaltll)' stall's, eartliat' Olltp UI
CHAPTER 10
tl K. 16-3.
co 20
~
:5S ~
u
~
• • •
15 ••
10
• • •• • o 0
~ ~ ~
zs 5
.?
~ ~
•
.~ ~
::J
•
i\
,In'''R1'''''1;.... n 'JTt"Loli.." Mi,"
1"1\00,,,,,, till' dl~""r"'ll't· ..{ hd"nu 'll" and i."Io:.. •.,.",,,illl" K" "' '' i" p.alio"T,h "'i ll""'1 (.1 ""'MI "'ill> l"llh mikl (o) ...od ............ (. l " "' K'OS!iW .-..nlia· {;til" re-, It"n'''' Zil" . R.:\. ;UM! 1«';,1. P.R : l .iclo:.. (;l.i'M' ki lM-til:s pn..1il1...I I~' ;IMI.M-,.,,"i "" W"..."
cl..ara,,("f' , H.-pri"I...I. h~' prrm i..i"" or 11,,· ~ ...... .:,,10:1 ••,,1 J,,,,n....J "I" M...Ii..;", ·, ,29'j :l lfil~
•
1111.1, 197'1:.)
00 0
0 0
5
10
15
20
lndocyanine Green Clearance (mUminlkg) alltl thr-refon- Itc'Ilt 'n . This nll1~t' is almost pat it·ub. TIll' hel );ltit' tlow, n:rtainly ~n·a l r-r than till' nUl ~"· of lu-patk- hlood flows in usllally ahou t I~ llll JlI1i n/l;~, is unlikely In fall to a vahn- ll-~ lo\\' a.s 2 m l /ll1i n/l. ~ h.......IlISl· ....-vr-n- anoxia Is "'\I')('{1t>tlln result at ..-cr-n lrigherIlow rates. 11t·1);11t1(.''l.·Il11lar ell7.)ll1..· al1hit)' is llllist p n illailly al.... 1 depn'sSl'l1wlll"lIlli·rfusicm is Sl"\·,,·n·ly ..Iimillisht>tl: thi s \'o'tlllld furt he r dt·pn·ss till' (·II'anlll('C·s of both lidl)(".tilll· and indol_').lUin..· ~n,,· n . As Iidnc:ailw 11;1-'0 a narrow therapeutic s\i mlow (S1'l' Tab l... l.'i -2), dOSiI~t· sllould Ix' reduced ill patients wi tl l l'C m~t'st iw ('anlial' failun' if 1111" risk of tmi dty is to 1)(· k"'pt low .
,",,"S('
RENAL DYSFUNCTION In pat it'lIls with l'C lmp ro1l1io;c."Il n-ual function, urin al) ' "'\{'n1ioll of t1 m~ is dumuislu-d. TIll' IIf reduct ion in n 'lml d imillat ioll depends on till' n -duct ion in n' lIi11 fuuetion, ,LS sllU\\ll in Fi ~. 1fi-....4 for l'l·fl,pin...., a filurt h-l-:t'lll'mtion l't'plullosporin illltihiotit'. \\'ln-n tht, usual i.lII. n "j.,rinwll of amikadn is ad millislt'f('{1to a pati e nt with n-uul fun ction that is only J7ll- of normal. till' d OlI-: accumulates eu't·ssi\'t"ly. a.s sllll'\ll In en ....'t· B o( Fi~. 16-S . Tlu- fj~lIn' u1....1 n 'm imls us Ihat tilt" ..-xtent of 'll.'t 11111ulatiu ll delli' lllls on bllih Ire(I'WlIl'Y of administratiull allll lJalf-li(e. and that the time n-quin-dto appnl;ll'h plateau is a function of half,lilt' unly (C hap. 7). lI a\i u ~ a mul'l l louJ.:t·r ha lf-Iif..• than llsual. till' tilll!" to n'aeh sli·ady st" Ii' is mud, Icml-:t'r in II,is p;.ltil"nl than in a pt'(! 101M' Il1aintail1l" l. dq~f(",'
CHAPTER 10
'54
. '111:' 16-4.
Creatmine
n ... I1 M'a ll .......' m,. {'>l'.,.f,-p;"....
a ...-pI...Jc..
Clearance
100 1
{'t' n lr"ti"'H i lll" rn,lil. ~ lO r
(mUmin)
I.'"" antil,;nh, ', an- ,Iiff" r-
0,., 1 ill 1""'it-uh "" lh "ill); n~ llo:1-tn't"S
" -"
a I I " I-",~ ,.. ..... ' ...-r 3(). ",I,,_ n M' \" " jo" 1< "',_n' Ii:n"'I"'t1 ;l<'O Jf'< 1i1l1l: ,.. II,..;, n..•... " n ..1t-r\-. tlinint' d.·..r........ •0lI,.... /i " ", ( /ru i,, ). (A....pl ... 1 fn>'" Har hhllip . , " .11 .. Knup p . C .., .. F"'Xl"', ST.. ~ l af7.l.r. G.R.. <: 1I~ . D .H.I'.• ;I'MI Piu", .." , F..-\.: 11...n "..·
10
,
"
'
.
-....... ........ <.
1
<10 11- 30
'"
•
31-60
61-90
('(.kilwt i"!i u f (,(·{(,fIi mt· i n suh, ,'(-h ",i ll, n·,...1 i"."tlK...·'K':\·. e li" . 1'1,;<,. lIlan ~ .
>90
n "'r" Pl:2&l-2'fi. 1991),)
0.1
+--~-~-~- ~
o
6
12 Hours
o
12
16
24
1'111:. 16-5. SLti •.ft " f ,h., .." ...."'1 o f arni!<.l. . " If....· in tI.., I..~· "ith Ih' M' f"IIoM'inR" r.-s;n,,-n " f .';IM' "'II: '''\T'~ ' I i I,r in .. I"" M-nl
rill
"'1.......
n ',,.J (11 "<1i,," is nllfT".. I. •"
in a fUliI·"t
...... '"
;UK (
~ ...... ~.
;",, 1 " .-iI:!'1 ;on' II..· ...." ..· 1..,1 ... t · rt'l' llJ f"'''1M'' ' i-~ I ':'~ uf 1M... • m;ol. l~ oIun~1 (~ ".~ ... S , Inl•• " "M"1< 1M.!'" ;od. mini.f ratioM ' i•• i "lllLot,~1. l1" ' lIun " lti h f·!if.. i. .... ."',M..l to I... 2: lor. TIM' 11" an'
.1.. "....
,1M' ;l",r.K1-' 1)/;0"';0" \......"S,
24
36
48
60
72
Hours
Deaeas. in Clearance 111t' r-k-ments of the problem of renal dysf""l1ioll an.' S1l0\\1 1 ill Fip;. 1f)....U. Ct·rt;17jdilllt· clearance , 11111,0,,11(1 clea rance here hr."l.'
unchan ged. In what follows . em phasis is placed Oil unbound rather t han total ch-amnc..-. This is not onl), because the all-im po rtant unbound roncent rut km is n-lated 10 unbound ck-arance bill also be cauw . for man y d n lj:!;5, fi' varies in n-nal dist'a.'it·. mak inp; interpretation !>
CluM) • RF ·
Clu.~
CH.6 PTE ~
m
16
T Ilt' nihil of tilt' Iwo is IIII' n-ual function Off') in tln- pa tie'nt rdalin ' to Ihat in the Iypiml pat ient. l u tln- typical p atient. Cl"'n(t ) is a fr.1l1ion,fe(t), of unbound (n-nal + nonn-nal) ch-arance-, CI",(I) .
2
Uy t'l: lI l1 hi l1i n~ Eels. I end 2. till' nubouud n-nal ck-arunce
ill tilt" path-nt can bc'
n-lated to
CI"' (I/ . hy
T Ilt' 1lt'\1 Sh' p is 10 ('(Illsidc'r tlu- unbounc] clcanmce II)' nOlln'n ;d rou tes . Cl"' ,\H' In tilt' I~Vit'al palit 'lIt , it is
O n Iht, ass u mption tlnu CI" ' ," I is 1101 dlangl'1l in renal d iM';l<;.t ', its value ca n ht, c'stimalt'(l for lilt, pal it'llt by laldu g into account his or her agc' and u 't'i)!hl. Using lilt' app m\illlation m i t'('
(1 -10 -
A ge ) ' Id (r/) o ;
1fi60
for tilt' factor II)' which nonn-nal cleur-
t1t'\;ah's [mill Ihat ill tilt' t~l)it'al p.uicnt (C hap. IS), its value ill tilt' lndlvi dual pat it'nl
I M'('( IIllI ' S
5
6
H it. 16-6. 11M' h~OII ("1c·......,K... ,,1" IIIt'I'l:1,1",1c"'1'1)ri o . ("c.' f1....id im.. . ",rit" hno'OIrh ' with n .... l in ill .· d" "r."K~· ill OIlo:"'''P IIf 11l1'"'''''1'h ",lh '~;nlo: .Ic·· lo:rt.... 01" n;-rual fUlK1io". :"ott· 1....1 ""11t· d....""'M~· lJl·h'!t' rt'l:1>lj"'h....l 11..·1l' l~ 111) rt'lW I""' K~ hnn . t D r_ Tl I"nlll1 tI....L.I" nf,.." 1>..1.'". R.• \ ·n ....
150
•
2
"·"lai,,.
~
§. 100
i
•
T it , Roan. A.M., 01110.1 Tt'T1",,,,.J. E.: D'_ J:r ;Itt· f........flv.io.lilll. · ill p;atin'h with im(lOli .....1 ...·n..J fundi-",. 1':11..." , J e lin. 1 1'OIn";It~>I .. .)'''.5!l; -
•
jU'>!I1I.. nl
~
filr.i. IWi.l
~
E 50
J
•
••
o +--------~
o
50 100 Creatinine Clearance lm Um in)
150
( HAilEI1 10
'56
Fur a ~\'t' ll
On sll hs lit ll t i n ~ Ells. I to 5 into Ell' 6, the rollO\,i ll ~ usefu l rd atinm hip is t1t'riwd for R,I. lilt' 1111110 1111<1 dt'ura u{'(' ratjo, C l..f,(d )/C I .u(t ).
11 '40 -
Agel ' wIId)O')
7
1660
Tln- fi rst
tN IJI .
RF .J(o(O, does
not
Incorporate
il~('
und wl·iJ.:llt t1in'(:t1y.
1 )( '<.~lllW
HI" is
("Slimalt't l From crr-at iuine clearance ill tilt' dpfull(.1 ional palit'llt rt'lalin ' to tllal o f tilt' t)'p it'al patit·1l1. A~t' and \\l'i~ht , of course, play a m it, in de!t'nllilliJlI?: tln- \1.1111'. Fig. I fi--S:\. illllsl...a tes tlu- n -Iations hip ht'twt't'n l~d ami n -nul fw lt'liou for vahn-s of j d O in ;15.'>-yt·ar-tlld . jO- k~ pa tit·lIl. It is appan'lIt that [(.I d lilll~t· S the most wit h n-nul fllll(1iol\ wl u-u fi ·(t ) = I am i is unchanged wllt' li F (t) = O. The- vahu- o f j e( t) is, liy dt·fillilio ll,
8 d nt~ ill tln- t~'P i('al(l
when- CI .R(t ) and CI .(I ) an- ti lt' n-ual and total ck-umnces Hf tilt'
9
. ' IR' 16-7. 11"0.01. n"I\ « ·n,,1. am i ' nlal ""1• • ,,..1dt·..r..... ~.... t.. pn ......~1 n-L.oti\~· I" tl..· t"l al "nl• • " .. 1 d ,·ar· ..,....." f Ii ~pi<,.] r-o-«." 'n,,, « 'n;11".· "f 0.2. n,..
1.5
i'" ·........
......·,," ..1by ...",.......1 ('1o''''''''''~'. I" a
,..1,1<' of 1,0. "~"'1' tI..· n·na!fur..i'"'' i5 th..1 of Ih.· t:.pil.. u pali' '1II, In , hi" itl" \tr.. lw,,,. ...,oa\ rlJl"iwm ,......... i" ..
~"'P of 55-~"'df""'1. 71 l-k!it palw·n . S,..,n',oal d. ·..nt...... ii, "f (~", ,-
pN·" -ti tu d , llIlK" witl, .. jot" am i ,,"';1(111 (<:1"",. 15 ).
o ¥---~---~--~
o
0.5 1 Renal Function (RF)
1.5
CHAPTE R 10
2"
DOS' AS!
B
A
fell)
1.0
0
~ ~
0 ~=
~ ~ ~ ~
-
0.75
025
~
-'" <;: " ~ 0 ::::I ;;:; 0 0
o~
g
~ ~ ~ ~
0.5
0.5
D~ ~ ~
",1;; - ~
~ ~ ~ ~
,.
~
0 25
0.75
0
1.0
•-r-•
"
~
felt) 1.0
5
0.75
4
3
2
0.5
1
0.25 0
0;
«
1.0
0.75
05
0.25
0
Renal Function
,. 0 1.0 2
«
0.75
05
0.25
0
Renal Function
H I(. l fi.-..'I . 11,,· .·,"·"I..f ,I........"... ill"" 1"",,,.1.·1.·....-........-. (.-\). ..".1.um" I'" ".L"lt i ' K'Tl~"'''' in l"o.If·l;f.·. (Ill.,.. "" ..1 I,;,' ...·".,1tl"f'" wh"" "I.., .1.1,..,,,1,>I, II,,· f"",1Mo1' IIfhio""';ojl,,hl.· ,1....1: ~llK'IIn:.. ,·",n1,..1i" "n,..· "'K~""'I:< .. l.ji1n ~,~ , . 111,,1 1:,·",·n,,11,\' ,Ie....• ", IJ'" I"",nl " ,,,,I.I , ,, ~ I...· ,..,,,.ic"·.. ..1 ""I.... II.., ""t.... ,T\••1.".. tI..· I.."..;""..,laI "'~ I, ..l li,..·. 11,,· (·ak-ub l;""'. h.",' I....·" IIM'I.· fur a ,;,u. ~( p"h" ,,1 "f ",mpa hl,· ..(•. '" a ~-pkal patio·lIl. 11M' " "I MIIIIMI \~ >Il1 n ll' (If disln ]II,I;"", "f tI,,· <1m\( i. ~'1>t " ", . 1."" . 11..· ..· ·, 1 · 1" ". ,\ , I..· ,."" I'i".oll< "ffi -il ) ..".1 n·,...1 f"' ,,1i"" flor whk'," " i" ro.,,·..f ",1" " ni,I...,I1<'" 1 .,,, , I,,·r"l..·" lil...IIYI' n ..1.1'1.
wln-n- " 11(11 ) a nd ' '1I(t) an' tilt'
lI11bu!llld \lll ll Il W~ (If t1i ~ l ri hll t i un ill
tln- patu-nt
wit h n 'na ]
di !>t'a~, ' am i ill 111I' t~V i('''] pa til' llt. n'~p('('l i\l' ly,
AI"" . n-e-al] that \ 'u 1t,IItIs tn ' , II')' ill t1i n "t1 prop ortion tn 1....ly \\l.'i~l l t . If n 'lIil] Iuncnon tlu-u
dnl"~ not afT,"t1
"u,
10 F i~ll rt' I(~n
Illust run-s III<' t1"I)I'lId" I1('" of half-lift, o n 1..,l h n-nul funt1inn am ] Iractlou
t' \(Tt"t('t l lll l(' l l a n~ ... 1. :\'otict' t ha t fo r a dn l ~ e xt'rt"tt'(l t'ntirt'ly Iln dmn ~t,(1. half-life dl ,ltl~t'S tilt' 1ll0~t wln-n n-ual [uuct ion app m",,·ll('s zem.
An addi tioll,,1 poi nt I u-t"tl.s In lit, mad" wit h fI-sp' '('1 tn data ''''t'pa ratt'ly for its d t'lw ml t'II,'t, O il a~t'. wt'iV;ht. allll l)t' rl.a ps n -nul t1iw 'lS" ,
Estimation of Renal funrtion COllluum[y I'rnp loyt..1 IIW; lS ll n'~ nf n ' na l fun ct ion a n' h...S1"t1 011 cn-arirum- II ~ Il s('fu l m '~~ IiI'S in its d, 'a r.lltt't' \ 't'nl llI ,'n'atinim' a1o nt, ruther than [rum 1ll,';lSlln'IIl,'lIls in 1" ,tl. ptlsma '11111 urine. :\ p,;\11 From tilt' t'\l m analysi ~
CHAPTER 16
involved. incomplet e urine nJ llt'<.1ioll is a major p robh-m n -su l t i n ~ ill lilt' underr-stimation of crcannlm- ch-urancc. Senun <:n ',I!in iTw aloll!' can 1M" used h' "i.'OIIISol' its daily production is ma tdu't l hy its elimination under nonnal drt11Illstan('('s. (AlIISol'l"llIl'ully. Sol'n un ('n'a tilliIW is rdah"tl lu (·n'a!illint· ck-aran ce hy
Serum creatinine -
Rote of creatinine production Creatin ine clecreece
11
Tahl, ' 1fi- 2 '1l1111llari/"'" sonu- o f tilt' n-huionslnps ('urn'nt l~' found to appm-ximah' enutuum- (·II·a(;lIl('t' fro m \I' n UIl r-n-at inim-. l1]('S(' n-larionships Include com-cticn s o f en-at[niur- p rodrn-tiou lilr a~" . \\l'i ~ht. and gender. It should hI.' e mph'L,iZl.'t1 thai tlley a rt' mos t al'('II(;I\I' for illllh-idual, \\i lll all a\ c 'ra~, · muscle- mass [sou rce of l·ft'al illim') for tlw ir a~t'. wd~h t. .urd Ilt'i ~ht . For "lIl ilc'ialt'c!. h h:h l~ IIlm(·ular. or oht'S(' ad ult p atients , POOT r-stimutes art' " h lailll'l i. For Iii" ,, · pal it'll h a u, 'alillillt · dt',lf
RF - C0dl/C0~
12
wln-n- C l .,.,.(t! l ;lml C I ." lt ) an' tIlt' creattnnu- dc'ar.U1(1·s in this palil'lI l am I in IIu· pal u-nt , n " Ill 'l·th 1·I,\".
t ~llie.l.l
Adjustment of Dosage Regimens T Ill' ;11h-m"thn II,r udju-tuu-nt of maintenance am l lo;ltlill~ doses in pa tu-nts \\ i lh n-nal fllndioll imp,lim ll'lIl app ly, ;11 prilldplt·. 10 all dist',L'it' cnmlitinns in whieh d mK r-liminuriou is all,' n·,!. For 110 ull ll'r r-oudittou. hm\l'\l "r, is t!l(, adj 1lSllIwnt n-qum-d iL' n 'mlily p n-dicted
and
\I i1inl t' llilll ('(' Hah'. '1'1 11' simpl('sl \\~.ty (If l"l )lI('t.' i\i ll~ lilt' adjusl llit'lit of a lII<1in tell,Ul(,(' ftogilll"11 lilt a p.un-nt wil l, n-ual illS ll ffil'it' lI('~" is 10 mai nt ain tilt, s< UI1 P an"r.l!{t ' unbound (~ ,ll(1' lI l raIi01l al ~ lt 'atl~ vlatt-.
ell......:
,.bl. 16-2. IJtlm.tlon of Cr• • tl nln. CI• • ra nc. l. A...lh- .... Chll.. ,..·
Ad -" :20- (f
,ow''''
; :Y.:l"'
""~
., .
12 X Se
I i
,"":J"
J 'J
j,o-
.....,
...,. ~"'''' f....'
... ~ ..,.,
..,..,., b ,'• ......",. t.-A,_-<1' ". ......
Se-um «ecnoee
~
. 0 AS X He 'g~' )( ( \\'e 'JI-,l) Se
.. '" ,.." .... "'''''''8 j'>3" ....".-J .. '"'_ P>..". ]7 CJ'. ?~
l~_ '~h""""
W~ghl
$e
11 40 - Arl x 'Ne'g",1 85 x Se-tum C'M"O,""
... lYO>l'-.1 ...... ,C~'JOO'J
.v,
1 23 x p AD - Agel x
11 .:0 - Ar1 " V\ e y h'
""''''-...,,.J ..
_r ,..."".. ". t '
.".
?o
42 5 x Heighr x (We>9h1)" 70
$e
"'"
,""
"'"
"'dapotd """' ... _ r " 1 4~1 ~, r9 7 8
boo too
<J ~ cJ- -"9 , """_
~
S
.,..j-.-
c~ . .. " " _
'9
' 1 r.... """"""""'\I'_boo ... ~to.o>_n'1>-""O:X.O''''' • ""'dcJrord -g-ob
CHAPTH 16
13 Halt' o f udmiuistratiou ill n-uul insu llid t-I\l:', (lJ.\tlt)(d) , compan-d to the us ual ratt' (If ad ministration to till' t~11kal patiellt, (I)u!t )(t ), is then
ID"'/'lidl
C"MI
IDMl
14
when- FIlI i am i F(t) art- til(' bilJ.t\'ai l.ahilitit~ of t1nJg in tilt" path-ut wit h r enal im lillid l'nl''Y t ~]lil..,l palit 'lIl. rt'spt'{·tiwly. \\llt'li hioil\';,ibhility tlOI 'S not d llUlJ::t', tlu- required ran- of administratioll ill a patu-nt with n-nal d~sfll lld i oll is
and in tilt'
15
Till' n 't!lldillll in dosi llJ:: r ute- is rln-refon- SI't'U to dl' pt'ml only 011 the mt io o f unbound d t'aralll'I's H,I' Asso(-iah-t1 with tht, n-ductkm ill n-nal fnlld ion is a p ml f)ll~at ion in half-lift" Wllid l IIIt',lItS that till' tinu- to al'hit,\'l' 11ll' dcstnd plateau is I Ol1~l"r the mon- seven- the dysfulJ(,tilln (Ell' lu}, Thi s tl,t featun- is Illustra ted in F i~, 16-9 for constan t- rat e ad nnntstnmon. III prad iet', admiuistrut ion is hy (Iis(;n-!t' d(lS(-"s and ",Ijus tlilt'lit of a maintenance reginu-u llIay II(' ITlt'tl hy a faetc r o f 6. TI lliS. tlu- lIlainh-nlUll'- rt-hrimt'lI Ill i~ht he OIl('of the fol1u"i n~: ( I) dush l~ interval increased si\fnld , rt '~i nlt' n : .'iUII 1I1~ (7.05 TIIwKg: X 6Ii k ~) 1'\ '('1)' i2 h r. (2) Ti lt' maintenance tloS(' ma)'
RF 1.0 ;;-
~
0.5 0.8
0.2
~
u
~
~
U5 0.6
0.1
" 0.4 C
. . ~
0.05
0
E
5" e ~
0
E
0.2 0 0
5
m
W W Time/(Typical Half-life)
~
2. .
CHAPTER 16
he- n 'tlul'('t! hy a fact or nf 6 , n-w ult'u: S.1 lUI: t'w l)' 12 hr. (3) Hoth , ltlSi ll~ mn-rval alill main te nan ce.' t1n<;t' Illay he:' adjusted to n '(llIl't·tlll· a\ 'I · ra~t· dusill ~ rate sh.fold . " 1.';lIlt'lI: ('. ~ .• 167 1Il~ ("'"('1)' 2-t hr. TIl(' typical half-life of amikacin is 2: hr. so fur tln- pa l it'll l under l't lllsitlt' ra tio ll the-half-
life is prulnn~('(1 shfnld to 12 lrr (Eq. 10). Fi~. 16-IOA is a , kd d l of t i ll ' amount in tluhCKI)' \\; 111 linK' fo r the tllR,(' lIlilinlt'lI aun> rP)..';IIlt'1IS con sidered. ~\"t'll Ilml 'lhso rp tion from A lth ()lI~h hnlh t i ll lt' to n -ach plalt·.m an d avplate-au an' the sauu- for atl tlm-e n..·W"wm. tlu- p il1 un' is \"(' 1)' t1i lTt'rl'n l fll r 1'<1(:11 0I1t'. Clearly. dlan¢ ll ~ tilt" interval to th ree
til(' t.m. silt· is ('t)lIlpldt' ;Uld Instantan eous. era~(' amo unt
500 00 400
.s
~ 300
.'"e" 200
i ll
hody
,, ,, ,, ,, ,, ,, ,
,
~
"
0
,, ,, ,, ,, ,
..
.s
400
~ 300
'"
,,
« 100
,,
"
,, ,,
e 200 ~
0
,,
E
« 100
---
0 0
24
48 Hours
0 72
96
, B ,,""'' ,, ,, , ,, ,,, ,, , ,,, ,,. ,
500
A
"",, ,
,, ,,
0
; 11
0
24
.N\ ,
.
,,
'.
,,
--
48 Hours
,'
'
'.
'
~~ - ,
72
96
I'le. 16-1 0. Sh 1d , nf tI... '''''1111'''' "l "",i b •.;" . " If" l.. ...I"i .·..lt·1l1 \ ill 1111·111111).' .. ill, h nM' ill " 1>;11 ;"''' 1 " III · n 'na! r'"I11;I" i. 1 1>.~q. ,If 1111' 1~1>it...1,-..I,...., silt"'" lin " n 1.";"" ·'I.' ..;111111'1 ttl I ",III w;II' IH) .. .5l . " "'1: 1< .....10,,1:,t. n ..· "~lIh-'''''l(~ 1't')(i1l" '1I.' om'; ( )-.5( J) "'I: (.... .~' 72 lor; I"ol"rt..l li,...) - ,lj.l mit (..... ~. 12 J.r ; (· ··)-. 11>7 "'I: ~. 24 I,r. S 'Il" ; i.\'. 111 >11.. ... lmi" ht r"t i<"lb . iIllUL." ..I,
CMAJ'l£ 11 10
26'
pa rticular ( ",1St ' IIf am ikalin, ha M'(1Oil ('Xpt.' rit'I1("t', lilt' manufacturer recomuu-nds III It changiuj.( lilt, uSllal h .l(linj.( dllst,.
General Guide&nes and Umitatiolls Eu"t'p t for d m gs \\; 111 \'1'1"). Inw Ilu'ralx'ulil' Indkes, a reduction of les s than 3f)l;f in till' d osing rail -. Il~II")'. ConM'lllll' ntly, ,lS 101lj.( us lilt' fraction t,\('ft,!t'(1 t1 lll'hall~t'( l in t'Vil'al l'li.llil' llts.ji'(t ), is O.3fl or less and ti lt' ll11'tahlllilt 's an' illat'l iH', 110 d JaIl~l' ill II ft1.'illWIl is l'u llt'(l for. lI,l\l '(1 0 11 n-nal fUlll'lio n. rt'~art ll(' ss nf IIU' funct ion. Simi larl)", rt~artllt'Ss of tilt' ('()fltrilmfion IIf ti lt' n-nal mull ', if n-nal flllll'lio ll is (1.70 o f tilt" I, Viml \1II1It', Ull dJan~t' is 1\('('(lt'(l (St'( , Eq . I ,'; ), 111t'S(> rt't'(lllllllt'lldatillus an ' sUlllumri/..t't1 ill Fi ~ll n' If).....I;A . As n-nal Funcnon a ppnMdll's r:..t·rtl. tln- importance o f nonn-nal dl'am nn ' increav-s. J I OW( ' \ N , lIo lln 'nal d t'ar.iIl("(' lIslIall" vari es w; .su d at('ll w;lh accu racvof measureIIlt'lIt (If rt'na l funct ion. TI lt' thin l relates to IIn- stahilitv o f renal funct ion with tillll' . 111t' flllld iull lIIay 1)(' illlpnl\; n j.( d uri ng convalescence or dt 'k riomtin j.(. All thn-e- p robh-m s ereau- 11IIl't ·rtaillty in prt 'l lit1 i ll ~ t hl'i;t~t, n 'fl" in 'lIlt'llt s. A Fu rther t'l'lIIplit·;ttioll ill pat k-uts w;lh M'\"('n' n-ual ha\"(' lint !M"{'n l'llilsidt' f('ll, Ht' ual fund ioll is tlllly lint' lIf M'\'I'r.11 MlUrt't'S o f \1tri;tbilily . :\ dj nsl lllt'nl o f t1 n l~ «d m in· i\ tmtioll I"Lst'tl lJll n 'lla] fllllt1ion alllllt' lIlustlM' put into IM'J""ipt'l1l\'('.
262
C HAFTH 16
Furtfter Considerations Heual d is.<'a.<;t· nflt'li alTt't.'ts ilion' t han jml n-ual ch-arancc. Furthermore, {1 J1l{'U ITI' n l di st'lL'it'S may alte-r d()sa~t· requin -nwnts. Di~()llill binds lIIuI-II less to lis.slIl's ill un-mia. rcsll it i ll~ in a smaller volunn- of dlstributtou iUld it shorter- half· lift· than that p n '(l il"ft '(l From
loss of n-uul function. This dec reascd nssue hilldiu!?: reduces ,h(' hllliu!?: doS(' n-qum-d hut 11a_s little o r 110 dT('t:! Oil tilt' mai lllen,lll('(' dose I lowt...v r. th t· pn'st 'ul"t' of St'\l.'n' t1 l11gt'St in' ca rdlac failuft·, a l'tltlt lititm fur which the dmg is IISt-I' !. is 'Lss.od a!t't! \\;111 decn-ascd uu-ta-
boltc clearance and \\; 111 a daily maintenance dU<;;I~C n-qum-uu-nt rt'tllll't'{1 he:- ~ md tim! t'llpt,<-1t"'ll for n-ual flllll1:iull impai rnu-ut ulonc-Tlu- dJ
i
o
,.It~ 1...:l. ......... . .. CI"_RC I ....... .,. WIth MlitII • • tII h • • _ c.
V.I Ca
DI.Ift I_ f.II
t DI••• I. •
.
1'C)U",·,'i Of (llSTW$,ITlQN
M id 5eve<e
Ct t> + 0 Q.4 8< OQ': CI". + 0 02
·~"""':S;- .18
cWocaldalo J
"Cl,. •
~
~_
B. - o - ,
~ ,' «~ -4lJ'Q
e - doooota .. Vlw/l.g
' ~...-. ,j ~l<nod>okl~
vv
1971
"
JB + 52 Cl", 3 B + 52 CI".
f_,j~"""""""",,,,,,,,jP"o-x"'_~'I..,.._
~"ASE
CHAf'TH 10
400
E M
"-
•
. -il(. 16-11. Tntal pla." "a ~ ~~ ,I"r ) aud Il"na! i hla<.-k ) d .......a'l('M "f tI..•
•
anlibinlk imi1"·,,.. m
••• Total
300
~
~
~
•
c
•
E ::J 200
•
S ~
u
c
~ ~ ~
\
100
1
•
."
13
•
•• ..1l!!:....
0 0
• •
-
'. •
• •
50
..J • • • •' • 150
100
"'ilh
Ihal tho· tlmll: i. " .... a1"~rn ..ll o:-· n·"..1 hmlic4... ..,,,I
•
Renal
In("l~·a ...•
tI..· n·..al c" ·ar..,.. ~· ' ,f ·' ,Cr.... hl·I,.....•• diam l"'1rl ruo.'f'1 i,: add ( '''Kll~ i7.t't1 l t Il 1.73 m ,,( "n,~' ~" rf...T' .....a ). a nmrk"r uf ~1l1"'",lar Filt ralinn rate . Snrp risinj.,'ly. tlo.· l\Oo~1 dl'anll"~" d" n"t I" lTl·.....· in l'",raIk-l ...< ....I"'l1 ,..1 ( Slot" H I:. lfi-71. i" dil.. ti UIit that tlo.· - no" r('I,;. I" d ..ar .." .... "f tl,.. ,In ll: must il.. o,,'l"n·lL,I,,!i.' "'ith d....,...a.....1 n-na l function . TIll' .·'pl..nati nn I.
51Cr-EDTA Clearance (mUmin per 1.73 m2)
lhal Ihi. ;KiM!) ' ,......"..... ., "'i l l.
.1.•.
m 'lLl illl/: n ·na! f" 'lcticll1_ Th' i""' r' ....pl ;mli.,.. t ... ,10..1 m m.· n"" ....n",l ",.,t ..h" li,," 10"" I... "c~' '' rri nll:
(Adap'" '' Irom \''''1''''Il,·n. G.A.. \'.'rhi..I . I•. fh mt ,," . "~ Po Enl\Ooi "k'.
1. A. J.M ...,. K_II . "'rKl n,·lIn... :o.U:.;
TI,,' ph.." ......'JId"'..iu ,,{ im lp" "" m (lhic·nanwri,,·fun nllmichtM') al..1 till' n·na! o,,'I;~,jn ,p.'-pt iola.... inl.ihilo r d \a..tatin ",.Jium in ", mna! subjt..1S ar K! p;rtic·" ts ...i lb n-nal fail" .... Hr . l-
Clfn . rl,ar m;l.('ol .• J!j ; 11i3-193 . 19'>-l.l
creatinine clearance or wrutn creatinine havt' be en giVt' li. This kind of infonnalion is use-ful fnr initi alin g d m~ thempy in an indhit hml patjent, hul til t' \1Iriah ilit)' n-mainiug is often su ffid t'ntly la~.· thai monitori ng of plasma conceutratmn, ti l t' topic of Chap . IS. lIIay lx' prudent fur a t1m~ "ith a ua rrow th" rJ.jX'utic windo w .
STUDY PROBlEMS {Answers 10 Study Problems ore in Appendix 11.1 Li ~t
ami hri plly disr-m~ ~ i 1( .I i <;f 'ast·~ in ,,1Ii('h th t' pIJann,u'oki ,wt i."'i of dn lgs is known to ht' alte red. 2. a. Hank tlu- situatiu ns in Table 16-4 , fmm most impo rtant tn least important, for ('(msitll'ring a dmllgl' in a do sagt, regimen of th e cephalospc rins listed ill adu lt 1);1ti.'nts \\i lh \1tl) i ng dt~n't's o f n-ual function. Given th ai all tll.,S(, drugs have comparable therapeutic indkx-s. II...• anticipated change in clearance as tilt' hasis uf you r ra nking. h . :'\al111' th t' situat ion s in Tahlt, 16-4 for whidl you would rec om mend th at conslderatiou 1)(' ~\"l 'n to a change in the usual dosage rcgtmen. T. ltl. 1 6-4.
..
F't J!CE NT o 00Sl' t
,
ElC tfT£O ~O
A
CeIt,zo~,me
B
Cefon"od Celo"'Ondole Celoranide Cef!az'd me
C
o E
2B
QB Q6
BO
B4
10
5 40
20
'"
2. .
CHAPIH 16
3 . Tahh- 10-.') ..llIl1ll1otri/l.·" phamMI"lI\..i lll' lk uhst' rYatioll s tlf I",,. {lifT., Tt'n l Clp in id alla l~t" • ..il.,.. ill pa t it'll h ....u h ,11111 .... nhout Iwpatic d r rho<;is.
r."1e
16-5 .-
__
Oro! BoolNo,oool,lyb Blood c'ec-coce- n;"ull! 'A_ _ d_'-""loaIIA ~_ t
0 18
"""""'J e,..",g",..,' 6 nQo>- lo} IQl'.l
e-~
1..-_<1 _ _ ...... """' • • 06
1""",0.:- -4..(;."'_ . •
0_ ' 0 00
0 08 0 08
1 15
II
t ~.. ~"B:It
0 87 0 57
" __
t~d""""","",'"
.... 06 ... _OC
a . K I " ,"i li~ tlMI ,)t>llt;v.lldut· iUKI ITIl'pt'ridint> an' (·liminalt-c.1 prilllari l~' Il)' I K 'ratK: melothol i\ lIl. "lI~("!it a 1llC"(-hanism to t'xp lain till' a1tt'n'tl \..im 1 i{~ in Iwp.dic ci rrhosis.
h . E\.p l.Jill ....11Y tltt' oral hif)a\'ai Llhil i ~' of pen tazoci ne- is afT('(1('lllll ud. ilion' tha n Iha l l)f 1lIl'Ill'rilfillt-. -I 111 T alllt· 16-6. '-aricm" dat a UII fl Mlr p atients wi th \-af)in~ tkWt"'-"'S uf n-nal fUlIl :tiull an" li'Ott'tl. X Ullt ' of tllt' lII ts U1l(k'rgoill~ a dialys is proc ed ure.
,.We 16-6. ,.uiNl
""""'"
Age 1)«1" )
:::J,hl rig1 I
5efum
(em]
C'eot,....r>e Img/dU
'"M 25
"
18'10
" F
82
eo
I t<)
25
•• F
3 15 06 I 6
"M 15 08 160 30
Estimah' tilt' l'n'a lini lit' d c-arall(.'t" in (·'K- h of lI WSt· illdi\;cluak h . C " I('lllah' 1111' n-ual fu ndiun i ll each of tilt'S(' pa tien ts. Express n-nal function ,l'i a r;tli u of ('n 'a l inillt' d c-amll('l.' ill tln- palit' lll In til(" va lu l' {':\lx"(1c'(l in II t~ llk·.J 5.'i-) (·a r.
;I .
Hili. 7U- k~ 1);,l l il' lI1-
5 . \'am 'ulIl) "('in j<; dU )'\('1I for IIII' t he rapy o f a 17. kJ{. -t-year-old. IUIS-(:Ill lall IMI)' \\ilh \ Iapllylul'ul'{'al p lll'ulIlOl lia, wllil'h is n ·frad0l")"to ot ln-r antibioncs . Til l' cluld h,l" modt'fald y hupai n-d n ·nal fUliC.1 ill ll ,1.\ indicated hy a serum l'n 'ati n im' of 2.• IIIWdL. Allp rU\ imOltl'ly tj.,)Cl llf a df)~' o f vancomycin is normally {'x(:rt"ll"~J IlIl(:h all~c '( l . Its IlIllf-lift" and voluun- of t1 ist rilmlioll an- fj hr a nd 0.-1 I J1~. n>'I )('(:ti\'t'ly, ill a I)Vk aI 5S -)"t'a r-ol ti pa til 'nl .
CHAPT E ~
.
,
16
6 . T Ill' kiudit's (If IX'lJloxifyllim'. U 1 lt' lIIorrl.t'()I (,!~il' u!{l'nl p n -scn b -d fo r Ihc' trea tnu-ut o f p -riplu-ral arterial disl':L"l' and i utennit te nt claudicat lou. is affected by cirrhosis. T ahlt· Ifl-, s!lows tln- d l ;\l1~t 'S in half-lift, aud ,\ UC follo\\i ll~ t.v. ami o ral (s ustained- release la hlt't ) admlui stranons. Le ss t ha n 1% is l'xl' rel l"d 1 1Il(-,hall~t'll in til(' uri ne. For till' jl ll 'l)t IS!.' of t h is probk-m. 11M' Ullly nu-un val ues.
,.ltl. 16-7. M.H·Uh ..... AU~" P....:d fylU. . I. H_hhy hltiMb .... CI",",tlc htl....'"'f ..... THYSlIltKTS ce-orc PATIENTS Inlrovenou~
dose (l 00 mgl 0'01 dose (400 mgl
0 8
~
0 .3
0 4 1 :!: 0 .0 8
(w~i nech eloo!le Iobletl ~AWI<xtod~ ~O"I8> '"
Po-<....,J -MI
0 52 !Io'o
+
21 :!: 1.2
14 :!: 0 5 1
017
l«o:;q,B Gorv-!O
330:!: 170 """"""' R , C ~ G a-.p~"""""
01 ~, ""'""' ''''''' -' ''''''--' '''''
par aun-ter valm-s ht'h\1."l'1\ Iwalt hy suhj('('ts and (:irrlloliL' IMlit,uts wi th n 's(M"l1 10 III<" foll{)\\i n~;
u. Dl'I N lIlillt' d ifft' rt'lIt1.'S in Ix' nhnifyllilll' kim-t ie
I . AhsOIv t ilJll 2. D istril uuion 3. E lilll ina lilll\
h . Brit'lly d is('lIsS how Ilt'p al il' cirrhosis is likd y to produce ti lt' dl;tllf:c ~ ('al('lIlah'l l for tlu- abso rp tion. di sl ribution , and elimination parameters of this d nl~. 7, T Ilt' plm rm;\('okinC't K'S of loraz epatu . a !x'II:f,odi;u.l,'pillt' \\i lll tlelllo nstrattod t'llk ac.·.y ,L~ an a llXio!yt i<-', aut kxmvulsant . antiemetic, and sC-''tLa ti\'l ' hypTlot k . was studled in patients with spinal cord injury . Ti lt' d Ol~ (2- mg: t11)s(' ) \ \01." ¢ \"l' n ,L~ a sing:lt' I- In 2-min Lv. Infusion. TIlt' res ult.. of Ilu- st udy ill I t't mplt~l'S , par aplegics . and controls art' S U IIl ma riTA'l1 ill Tahl t, 16-K 1111' dOl ~ is bo und 10 albu min O.()9).
,.ltl. ,...... Lor.••ptI. . Ph.....c.kl....c h_....... I_ ......... wi'" 1p1_1 CenI 1_lury .... I. C..... I.·
c
SU5,K 1S
1"..;.....; .. 1)
Tt.>lrOpleg >c (n - 91 Pcropeqc (n - 0) Conl'ob (n _ 91
20 ~ 0 37 ~ 11 4 2 + 19
'-tIaooftop. Soogn JI ~ S ' Ell:>«>, 1M ""'o- ~ J I6 ~ I -M¢ l QQI
,
"I
""
1,6:!: 0 4 10:!: 0 .5 15 :!: 05 Doc~...-dooo
31 :!: 13 25 :!: 9 20:!: 12 ..
~.....,'I""'<JI<
a . \\11c'lI ~ \"t ' li or. tll) , tln- bil o;l\'aibhilily o f lorazepam is gUll , UShlf: tilt' ktm-uc d al a ill Tab lc' 16--."; and ;L\slITlling instantan eous abso rption. calculate lilt, mean pe ak aud tmuf:h concentrattous t'xpt"{1t'tl O il oral ly ad llli n istl' rill~ 2 1llJ;:: "~it1.·llti ly (t"\l-' ry 12
lrr). a typic,,1 rq~i nl('11 for
t reauucut of anxiety, in ti lt' tet raph-gic an d abk-bodu-d spinal injury) patients. U M' an average weig ht of 7U..kg am i F "" 0.9 for all sl,hj('('Is. IJ. Loraz epam is pri marily l'I iminalecl by ln-pat ic g;11I('lIn midation, Discu ss each of tlnfollll\\illg mechuntsms a.. a possih lt, expla nation for tilt" dt"{'n 'll.'il'll clearance of lor ,uA'Il;11Il ill patir-nts with spinal co rd inju ry, J, 1)('tTI ';I.'il ·d hepatic hlood Ho w. :2. f)c't'n 'aSl.'tl lw palo(1.,lIular Illt' laholic ad h ity , (1I1l
"w'"
266
CHAPTH 16
3. Entt'mlll'pafie l'),:lill g of tlmg l hmll ~h its g h ll'Urllnid t· ....illll('·" Ims of drug or meta bolite in f('(:~..s. 4. Inc reased biudi ng to plaMI'" pmtl'ins. S. TIl(> c!t.'a rnllll," and h.alf·life "allies for IIl '(.":li nidt" an untldvsrhvtlnuic a~l· ll t . o!lM'rY('(1 in six patit'nls wi th !It'I);llic c irrhosis and six Ill"altlJ~' SUhjl't1S . ll·rt·listl"l:! in T nhle 16-9. Tln- IW:llthy sulljed >; .... vre-, 0 11 an'l'dgt' , matched in u-nns fir agl' and wl'i~l l t \\i lh tilt' cirrhotic group. The dmg (2 mglkg) "~d." ~ \1.·n 11)' i.v. infusion over I.') min.
r.It•• 16-9.
1...1,,14_1 V.I_... CI_NM_ II. "_Ithy Celttrel
H~c CI",,_.I••IHIII.
Clecrcoce ImVmm/lgl Holf.lole [1111
1.1,16. 4 2. 4 6. 57,5
18,28,37, 43,78.107
0Adopood ..... ~, _ I . ~ Ckrog, ~F ~
n. . .u s«>-sn . 1088
Com>d GJ
H.lf-lif.l.. ,I. P.....h With
liMtII· at>
6 2, 8 2, 8 3. Q 5, 96. 11.7 Q
1.92,9 4.95,95 , 10.0
~ ,-. oI ~ ",~
....<.....,.,. oI "''''''' 0...
"'..... _ ~ ... ..........-.gad.
Do tllt·St, ohservations support tlw notion tha t variah iliry· in ch-arunoi is ~n'ah 'r in till' hepatic ci rrhosis than in its ahst'n('('? B ril · ll~· stat!' the 1Ja.\is fO I" ) U IlI" con-
pTl'St'IIt1· of
du_\illus.
INTERACTI NG DRUGS OBJECTIVES The reader will be able to: 1 Discu!>S the graded nature ofdrug inlet'ochoO$. 2. kcettaj" whethet phorrnoc mencs 01 phormocodynomics of0 drug. or bo!h. iscbeed by uocther drug, giveo unbound pIo.vno dfl.'9 concentrolioMime dolo. 3. AnhCijXlle the likely chonge~ in plasma and unbound coocenb'olions with time when Ihe phormacc*inelicS of 0 d,ug i$ cberedby concurrent drug odminiWOtiOn. 4 Showgraphically thecceseqceoce of 0 phormocobnetic drug inletOClion when the mechanism and the circumsceces 01 itsoccurrence ore given.
( ''UTll III O ll ly rt 'l"t'iw ' two or ilio n " dm~s concurrently. imlt"t'11, inpatients Oil an' r.lJ.:t> fin · d m !-:s d u rin!: a huspitali;,.atioll. 111l" reusons for Illultiplt' ( I m~ Ilwrapy ;lrt' many _ Our- n';l'iOIl is IlIa! dOl I?: com bfnanons han ' 1)1"1'11 found to 1)1' 1)I·m·Rei..:1 in till' treat ment of SOlllt' ('ond itiolls, i lld lltli ll~ a \1Ult' ly uf cardtovascnlar t1 i!\t·lt<,(·s, lnfectious, a nd cance r. Anotl u'r n ';(\l1I1 is tha i 1);ltil'n ls fn '(1Ilt'n ll)' sulTt' r from seve ral concurrent diSt'il<;('S ur (1)11d iliollS, ami pt11Ioxidty o f Ollt· or 1II0rt' o f tilt' admtntsn-n-d dm ~s . A t1wrtll1f'utic tim /!. i'ltl'mrlum has then oceurn-d.Tlu- IIndl'sirabl" t'l Ill~'I I IJ( 'I1('1 'S of a d Ol ~ inll'ra{'tinn lIlay arise Irorn a 1.11,k of IIll(lt·r.ilall(lin~ of, o r a faitlln ' 10 recall, th e mcKie' of action and til(' pharmacokineti cs of each t1m~; Illan~' undesimbhint eract ions t, Interactions an' o f a !)1)(' or of a suffil'it'1l1 mav;niltltlt' to he chnicra II,. im portant . illlt'r.lli iu llS 11t'IWt'('1I t1m~s wtthm Iht, hod, - ta ke place wtthout alTt'(iillV; ettlu-r tilt' II1llXlIIIld dOl/!, l'\)Ill't 'nlraliun or till' t1lt'rapt"lIlic alii\1!)' of 11ll' (ImJCi ill\u l\'('(I. .\Iso , lilt' dnsa~c' of lIIa" y d nl~s nc'('(lt11I u demonstrate a d ill i (~dlly si~n inCl.ln l d n l!?: int e ract ion cau t" (,(111111t' medinu lethal dose. Furthermore. man" alTt'(.ie-d pmc..'(·sSl-s and pathways of tim/!, r-luninanon art' " XI minor ttl ht, (If ('I1I11'('nl. Implid l in lilt, defin ilion u f d m /!, interact ion is lilt' c..,mc..'(·llt 111Ol1, like' t'sSt'llt iilU" all n 'SIJlJIlM'S of tilt' IMxl)", Ihey an' ~mdt1 1. The tlt"grt't, of in!enlt1ioll t!t'pt'll(ls o n tilt' 1'1 11I('('11trutton of lI.t' illtl·r.It1in/!, -"1)('(;I's and hence on dose and lim e, That a ~\"('Il tim /!, combtnation tlOl'S 1101 t'nSIITt' 111I'occurn-nce o f a clinically SiW lifil~,U1t illft'T;ltiiUIt is Illust rated hy
)lal it'liis
",("t, j\('
'toUl"
"7
.
,
CHAPTEl/ 11
'."'e ,....-eII•• 17-' . Pre.-.. htw
.t All
lhtlly ef 237 W.....rI ••YreeIellI .........._ DetectI• • W.....rI....... CIII_I Ny••••-
237
All po!1eIll$ who receoed chbol hydto!e dvllng worfu"l1 Therapy Those ~I!> who recewed c"b al ~'0IEt Ioi olleo~ 3 coeseccnee ~ Impou, bIe10 e-.Jluole ,nterOCloon ld,"ocolfy umIObie CIt mv/l,pIed,"'9 chor.ge~l
6Q
28
P()6e
· ""-xtod """' o:.xh-w ....
J
~~
......d-ug_"""' '''K(l~...-'''''_ C...
2]
19 ~d
, ....
141 )9-1 .16
l Q1)
tln- dat a ill Tahk- 17-1. Cilluml hy,Jmh·. a S("tlatin' hypnotk . is l llllll~ht til poh'lIliah ' tran sic'IIt1)' ti lt' ilulkua.L':ulaul (·lTed s of warfa rin. Yt'l in olily 2:2 of 2.17 pa lit'lIls. who wert- sl lld it'(l pms pt'(1in ·ly and who n't't·j\'t'·d chloral h)llmh' d llrill~ warfarin Ilwrap)'. was pote-ntiation o f warfa rin's (·fTt'(1 1II1all1hi~ IOIlS I)' demonstrated. 111t· rt';NlIlS fo r tht'st, d iffe n olll'(" in n 'sl'Il lll_'il' an' "'
CLASSIFICATION Om' s~~ lt'JTl nf d 'l..si f); n~ t1 "'~ iut emetions is 10 1I0lt' wheth e-r dmg rt'S[M IIIS(' is inl"n';L'it"l1
or decreased. \\l lilc' [•- rha ps d inimlly lISt·fll l, this d 'lssifl..alinn tltM... Uflt Ilt'lp tn tlt·Jim' lilt" nu-chauism of tln- inlt·r.l<1i oll . In t his book . int eractions an' d ;Lssifil'1l on tilt' basls o f wllt't1lt'r pha n nill't.lkillt'tit"S or phann'll't.. I~llalllil.". is aln-n-d. tX"lolsillllally. lxltl l a rt' dlilll ~t"li. Dist illti in ul..-twecu rlu- two is madt' hf rt'lalill~ rt.·SptlllS(· 10 till' IInlxlIIlIll pla.sm a t'lllll'l'U' tmholl o f tilt' pl.ilrll1al'lll llWl~dlly atii\'(' SI)("l:it·s. Xu dl 'lIl ~t· ill 1111' unI XlIlIltl l'lIIWt 'n lmlioll rt·slltlllst· t'll'\·t· illlplit·s it ph,tml'K'llkilwtic t1m~ iuft'fiI li io n, wh id l l<1Il a riModiller t1mlll~h a phrsk~l l illtl'r.Kiioll , slId l ;l" l'OIllI)('lilinll for prolein hi lltlin~ siltos, or t1 lrtlll~h a!te rt"ll physinll)"~Y, .sue h 1l" ,tlk rt..1 hlontl flu\,,' al ,ill ahsUllllio n silt·. TIlt' n ·sult is a dlan ~t' ill OIl(' o r 1Il0n ' of till' primary pharm 'K'llkilwtil' p.;mllllt'!t·rs, kil , F. \ ', Ct.#{, C I. II , whid l ill tllm alt t'",," till' St"l'lJllda.f)' p!la rm 'lld d nt'tit· paramt'tt'rs , slld l ;l.. half·lift, a nd I~·fon· pnx"t"t"tl in ~. a di Sl-1lSsioli of wlllli is IIlt'alll hy Ih t' uun l i ll t..,-m1;fm is \m rt J.wh ilt·. S t rit.i l~· s pt'aki n ~. Ihis \\l m l implit·s ,t III"t""l tffi'f1. Tl w ill!t·r.u1 inll ht·twt't ·1I " m t1n1 ~s . A a nti H. llIi ~ll l thllS 1)(· i1t'noted by A H B. An ('Xo'lmple is tilt' t'lIIllPI.'lil ion IX'''''''('1I two t1 n l~s for a l'lIIllTllflll hilldill ~ silt· 011 albu min: {)I\e tl nI~ dispI.K't·S hUI is alStI tlisp l'U:"l't1 by t11(' utlll'r. (;('Iwmlly. lIu..", ...'t' r. tilt' It'nn illtt 'mdl,," is inh 'q l n ·!t'1ll1lon.· hn:);l(lIy 10 iutl il'lllt' an y .~ ih l illi()11 ill wh idl Ullt· dnl ~ alT('<.1 _~ .Ultltll('r. Fur t·:>;a mple. pllt'lluha rb ital ap llt' ars tu rt't hll'l' tilt' " bsurp tio n of th e tliun ·Iil'. fu rtl'>t·mid... hil t th e n 'nlll d eOlrdllt't· llf pln'lIllhn rhilal
Ji'.
CHAPTER 17
INTE I!ACTING DPUGS
'69
is i1 K' rt';L~( 't1 hy tilt' d iu rt'sis pr odue-d hy fuwS('midt·. l l1is llIi ~IJI lit, regarded a-s a hic!;n'CHO/wl illtam1ioll alld lllay be denoted by A ~ B, Clearly, ill tht' case of mutual and h idirt't'ficmal tnn-racttous. tilt' measured resptlllSl-' of O lll' d ru~ caunot lx- cousfde n -d \\i tlum t also dt·fjnin!!: tilt' It·\"(·1 of tilt' ot her. \\1lt'1l ~\"t' n in sulTk it'nl q llanlities, tv.' l d m ~s almost ah\"d~"; affect t-;teh other. this may not lit· lilt' case. hOwl·'v r-r. at roucentratious achieved ill the rapy, For example, tilt' antihiotil' euocu-in inh ih its tln- nll' taholislll of th('tlphyllim', hilt t1lt'o phyllitlt', at duS('s nonll al l~' gin'n , d(I('s 1101 alTt'd tilt' rt' SptlllSt' OT tilt' pba nnaco ktncucs u f enoxacin. This Intcract lon is f/lli tl in'c1iOfwl am l mnv ll(· dt' lluh 'tl bv A -+ B. In a IInidirt't.'fiOlIllI interact ion . tln- un alTt'<.'ft't1 DOl!,": A. ('.~. , t·l1ll~ll'in. (".111 1M' n :nsidert'tl indt'Jll·mlt'n tly, h ut till' chengc in rl'sp(lIls(' of tilt' uffecn-d () m~ H. (' . ~. , tlwop hyllille. 1';.111110t II(' adt't luatt'!y dt'fillt.,,1\\i lhollt also constdNill ~ tlu- {1m{'l,'lltmtiou· rt·spmlSt· {'UT\"(' uf tilt' t'fT('{'f of D m g :\ Oil Dm ~ B. Esamplcs of d m~ inh-ract iouv are listecl in Tab le li- 2. '111t' material in Chaps. ~ to 12 form s tilt' basts fur
AlTERED ABSORPTION It was stated in C haps , .,\ anti i that tln- mort' rap id the absorption p n x, 'ss the h i~l lt' r and r-arln-r is Iht' peak plustua ceun x-ntration am i th at nei ther total ..\ lie aftt'r a siJ l~l t' dust' nor Ace within a dtlSitl~ interval at plan-au afu-r chrome do stng dla ll~t'S unless tht' hin,wail, ahility of tilt' drug is altered . Therupeutk-{'Ons("'!llt'nl1'S of a dmJl~e in t'itllt'r rate or extent of d m~ absorption wen- dist.·llsS('t1in Chap. i . Cousidcn-d 1I0W an.' situations in wh ich hio;mtil ah ility is alte-red. wit h eJll r h,l~is Oil l-!J; tI1 ~('S in a\·t'm~(· ptL~ lItli concentranon \\i tll tiutl': an alte n-d rate of ubsorpnou l'ha ll~es only the t1t·~n.'t' of f1ul1 uatioll around the a\l.'rd~e value. TIlt'S(, situations art' common in chronic dnt~ tln-rapy. T Ilt' t·\"(· uls an - iII ust mlt 'tl in Fig. Ii-I. Fi~u Tt' 17- 1:\ t1t'pit'fs tln- situation in which a patient sta bilil.t'l.1on Dr ug A. ItOW rece-ives () m~ B, which reduce-s tilt' hi();1\1Iilahilit)" of D m g A. It is apparent Ihal if no sle ps art· taken to change till' t1osi n ~ raft' of D mg A, its concentration falls 10 a lowt'r plateuu. tht· ti mt· I M'i n~ dcternum-d by t!lt' ehmlnatton half-life of thi s d rug. Suppost.· that it is tlu-u Ilot it'(·t! thai tht' pat ien t is Ill) l un~er 1 'It 'i ll~ tTt';att'tl t·fft'<.ti\'t·ly \\i tlt D mg A. illtd Ihat, hil\i ll ~ rt'l.'("til.t'l.1 tIlt' pmhl" m, tilt' nlT" Il( lill~ d m~ is u;thd m \ \ 1 1. 111t' t'()ft{'t'ntratioll of Dm~ A mJll ld t!lt'n f(·tuO\ ttl Ihe pn,\; olls plateau \'alue in 3 .3 e liminatioll half-Ih "t·s, l1ll'rdl)t'u ti{' {'(mtm! m lllld a~a i ll 1M' Tt·sloTt'l.I. Ah emat i\l.'I~·, on anol ltt'T(Il"l'llsion , in alllilil>(",1. II n\\"'\"('r, tilt' dall~t'r o f tit(-' t.,(lIl('t'lllration o f [) rtI~ A ri si n~ t('It) hi ~l , if tilt' t!osinp; ratt' of D nL ~ A is not f('a djus!t"(1wllt'll D nl~ B is \\; thd ra\\11, mu st always lx' kepi in mimI.
INTEiACTING NUGS
270
. ' ....w',
'\fU.l'<)f\;<,
" .....'"
""""" r
CHAPiH 17
By Inh'b11flg mono"'ine o.odo~. Itony\cyplom"'-.e potenhOIeS!he sympothom"nellc oc;llQI'l d
phenylpropanolomlne
Mutual -*:Il~ eIIecr... ChlorpromClZl1le rh '~ uplake of
guot'lelhid,ne or pc»lgOngloonoe:
OO<etlE'fgoc neuron,
Eocb Io-w<s the effec;:tlver>e$$ 01 ....-".' .....
. ".,.
me """
... '~ ""'n,:"'lI',<,
p.u.wta;
I1SPONSl
"''''''
r
, r
j
.... ... ' . '
f>/elocbpromode "'a,lto n, gwric emptying Epineph"ne decreoses blood Ibw 10 ,nrecl,on s,le oS lidocaine
CIITlelidne ..... NoeloproIoI
,
('meI!d,ne mllibon meIOp(oIoI meIOboli~ , e..pr~ as d,m,nir.hed l,'*PO» efled
Calcium ..... Tetnx)d1/'l8
Calcium Iorms 0" mldoubko com-
r
~
,
..... Volprooc odd
plex ....,;t!l lI!lroc:yd ne VolprOIC cod d,~e5 pherrvtom hom album,,' ,
Ouiotdine ..... Dtgo>o;,n
,r
Ouintd">e d ,~ d'gox,n Irom It_ blnd,ng \.lies
IMompofl ..... WtJrtonn
~Ilampll'l indocM
El)'Ihromyc:,n ..... TheopI¥lone
micrmomal en'Y""" Erytllfornycin inn,bors Iheophy4Ilne
r
CilosIOl" -0 Im,penem
C;1o~hn
rneIoboli$ffi
,,,h,bor.. rhe 'enoleeecb-
oIiWl of imipene
ceoc-ce. me
IlOl l!lt(;f elo
by
Chlororhiaz.de d,miniY-.es !l6CrellQfl ~
0 .....,.j_>o'\(JI
... 0'1CM _
01 hlhium
to.,Jlo,:tod d>\O)
~o~ ._
TIl(' ~ i hJ:lt if)m; j ust constden-d t· lI1 p lJa.~i7'(· th t • d t'p('nd e ll('(' o f tune scale o f events Oil the half-lift, uf the a fT("('h'1l dmg, Thus. fo r afT("('kti dmg.s "id l \'( '1) ' long ha lf-Ii, "\'s, such as p llt"llllharhitill (' 112 (If -4 d'l~'!i ) , change s ill n 'sp0I1S<' MI.' Insidious. and til(" C li ll i d il ll lll a~' !lot a\sociah ' lilt' interact ion wi th the causative dmg, which was e ithe r iniliiltN I o r stopped sOllwlimt' pn"\ifl usl)'.
AlTERED DISTRIBUTION TIlt" most common explanation for aln-n-d dt stnbunon ill a dmg Interact ion is displace me nt. Di splal '\'ll1l' nl is lilt' n-ductkm in the binding of a dmg to a macromolecule. usu ally a pron-tu. (Hotll s('l i hy compeuuon of another d rug . til(" di...placer, for l'OllllllOIl bind ing site(s ), TI I(' result is a n w ill the fract ion of tlm g un bound in p lasma o r tissue , or bOlh. Somettmes. himlillg is dnuinished Ihn ltlgh an allosh'ri c effect . TIle second d rug. hi nding 011 anot her si tc-, Indu ces a confc rmanoual dlOlnge in the protein , then-by ({'(luling the affinity of the first dnlg for tilt' protem. Occasionally, all allost e ric ('ifNi causes an enhanced affin ity ht,twt'('11 dmg and p rotein; dmg bind ing is then Increased.
INTERACTIJ'"G DRuGS
CHAPTER 17
271
Conditions Favoring Displac:ement Two u md ilions must l)t· met l)t'fnrt· sub sta ntial di splace ment ()C(111'li. Fil'li!, in Ilre- abM·Ill't· of a d ispla(·N. Ilw d OlI-: mu st l)t· hound IIlllstl~· to 11 p rotein. th ai is. its III mu st 1)(' Illw. Oh \ioll sly. if a dOl ~ is 1101 hllund. it cannot 1)(· displaced. Second. the dtsplacer mus t IIC(:IIPY tlu- majuritr (lf thr- hi ndin ~ sin-s. tllt'R 'by suhs ta ntially l{Jw{'rill ~ the' number of sin -s ami lilhlt' to hind Iln - d Ol ~ , This S('('! III t! ('Ilnd ilinll is likl'lr to 1)(· IIl<'t wht' ll thl' displace-r ( ){"t1 1pi t· s most (If the h i lldin~ sites. Tal ll(· I, ~1 lis t s " ,u g;n Jllps of dOl~s thai biud 10 ullnuulu. a protein thai ('-usb ahu llllantly ill ph sllla ( 1-10 W3 L: OJ, III ~ I) and in tilt' int t' rstitial fluids (2 10 ~ ) . x ot all d nl ~5 h ind
A
4 C o
D , -O
"
----------
3
H
i5£:1 2
0_
eO --- ------
,,8 •
-2
2
4
6
•
ToxiCity
Oplimal ThelaP)'
2
------_ . Ineffective
0
2
46
8
1012
TimelHalf-ll1eof DrugA
l Drug B I O~eA rI - -- ---- -- n --- -}~: :1
Dosing
~:e ~ 1--=='=-=-=-=-=-=-=-=-=-=-=-=-=-:;5 ~ :'
Drug A 0
Potential
-------- ------_ .
3
,
10 12
Druo 8
Dosing
"
U
0
, ,
•
4
L
. ·i!l:. 17-1 . Ah.·" ,,1 ah"''1lti.." A_ " " 'l{;o.> Do ,lt R i. ;oo; 'mini_I.·......1. tI..· hi"....-aiW>il ily ,,( Drult" i> " " I'K'O " I I".... ..·-half Fur 'i'''ph' n "I' K~,,1 to ils p","istlllieroll.....1..'n I) n 'l: R l. ... n.....,,1 (Ol-... II. ("...,,-). R. l'al it'1l1 >1.d>iliJ>,,1"" Dm l/: K, !\ n ;M""jU" I'· l"" ""- lllr.ati"" .. f D m lt.A i. ,.. II ..d lin.,,1i.".... lt u"h . tI... USII;<] ..... in~ r" I.· .. r tI,l>.Iml!.I. ... >t,I..." I I,....... ' II . (".Ie...). " 1M'n Dnll!: H il will..ll1n\l " tI,,·", i' ll l"II,·nlw l,,,.I,I.·m ii llliLor I" 1 1~'1 n m,i.I.·" ,,1 ill ..\
n..·
,,,,, ··ll;<]r
T.I.•• 1 7-3. .1 .... 1..... hl.ctMI D....... AI....I" O'VGS n-v.T sec ro »o CoYI£ll ~ oe o rwc SITES, OESIGNolTEO I ~ I
"'" ''''''" "" ClliorOlhiozlOe F",owm,oo
-'"
'- O ""d>et_
lodomeohac,r{
DidoxociMIII
Nopro~eof
G1,bencIomode lbupr<::krl
Svliod'melho ~'ne
l~,n
Salqk: acid
Napro-@Il
ToIbvlOmrde' volpoc ocid
Oxocillin
Worlorin
Tolbutomde
-0",
"..",.,."''-9' b«l to _
8enzodoOzepo ~
ac..ocillil'l
.-..
Peobeoecd
"ri"..
272
INT(iACTlNG OIIUGS
( HAPTH 17
In and 1ll'lln ' ("fllll l)(·!t· !i:lr lilt' suuu- pri m" r)' hi ml ill ~ si te 011 albumin. Alhunuu ami sOllie o l llt"r prote-ins han ' "i('\t'ml h illt li ll~ sites, ('<1(:11 ('xh ihili ll~ SO Ill I' dl"~n"t:' u f Spt·(:ifid t)': pos Sl,'ssill j,t all ad d k function is lint a su ffide lll (-m erton (or pn'(li<:t ill~ tln- ;ahilit)' o f (lilt ' ad die
t1m14 10 dispLu.'t· ;\ 110 111('1". ~ I ()rt,( l\ l·r. ('\l'1I t !lO Il!-t1J alnlC)!;1 ;111 t hoS(~ d m!-:s that t ll lll pt 'll' fur the- ....IIIU· silt - haw a hi!-:h affinity for allumun, o u l)' a fl 'w art' !-t('lwrallr lislt't! as t lisp lal't·rs . s!I<:1i us sa li<: Iil' add, \"a lp m i(' add, and p llt' II)'lhulazollt·. l11is list is lilllift'(IIM."{'a u"t' tilt' ptlsmil eence-n tratiou ad lit'H'd dll ri ll ~ t1 lt' mp~' IIIm t app mad l or ('M'('t "(! 0.6 III ~ I, till' llIo lar ("f lll('(' ul ral io ll o f p!,lSlIl,1 a lh u m in . F o r a su!lsla m "!' \\;111 a 11101"<:111<11' \\1..j?:" , or 2.''jO, Ihis l~lI ll't'lltmli(lII l~lm'sp(lmls 10
ISO II\WI~ T h is ccncentranuu is appruaehl'll durill~ salicyla te
dnl ~s an.' l~ llllllltlllly J.,';\'l' n in doM.'s ilppnlill:bill~ I ~ a nd 1)("('.lIlM' tlu 'y I)(ISWSS n:lath't'ly s mall 'Ulll lllt'S of distribution. III 10 15 I.. " 'jlh pllt 'u ylh lll;u.ullt· Iht' ptL'IlHI conceut runon ael.it,\'t'l l with lilt' usual d OM', HilI III~ ( \ ' = 10 I ,), is only 1lI1rlWL h ili I)("(, m st' its d t'antnl,,' is low a nd ha lf-li ft, is I nn~ (3 d ays ), t ht ' plateau comvntratton ult illl at t'ly adlit'\ '('ll is hi~" when till.' usual mniutcuance n '¢ lIlt'n of 1lI0 ttl 3(11 1 1Il ~ daily is atlmill ish'rt'l l. I>ispl a('t·rs sha n ' a ll t'Xpt'l'!t't l l"tllllTllIIIl pmpt'rty; i.e., tl w ir fil vahu-s d mn~(' wit h pl:LSlTlll concentration. \ \ 'i1h 1110 .. 1 sift' s t)("t.'u p i('l l hy tilt' cbsplacer. tilt, Fraction 11II()('t'lI pi ('l1 is <;('11siti \"t, III a d"lll ~t· ill IIII' concent rat ion nf di sptl<.'t'r. Tln-n-fon -. dtsplacers IIlllsl s hllw l1 J11n 'lIl ra tion-dt'llt.'IlIIt' 1I1 d isposit io n kinctn-s (C ha p . 22, DoM.' and Tum- Dt'IX'lI(lt'lll1('s ), SU f ar. t1i, tim1inll h'l' IIt'l'1I lHad(' IM'''' 't'l'1I displacers a lit! d b plal't'll dm~, h UI il sh llu M 1)(' a ppan.'nt thai thi s d :LSsifil'al ioll is urbitrary. Plu-uylbutazmu- is said to di splan ' warfarin fmm ulhuuuu, hUI n llly J,t'l.' UlM' tln- p l'LSlIlil (1)IJ('t' Utr'dIi01l o f pllt' uyl hu tiVm lt' ( HilI mwL: n.3 1ll~ 1 ) appn li,dlt's th.. molar (1111(1'n t ra lilll l of ,(Ihumin (0.6 Ill ~ l ) , wllt' rt·.l.' t hat of wa rfa ri n (I til .. mwL; 1l.On.110 lUll 1lI ~ 1) d,)("'i not . Bot l. dm~s IIiM ' similar alIilli!iI's for tilt" SiIIUt' silt' 011 alluuuin. ;tm l if tilt, l1111('t'n t l'llt i(lIIS wt-rt- n-vr-rsed. warfarin \\ Ullld IM' l , tllt'll 11lt' t!isp la("t'r. T Ilt' (,"tlud usinll s dl'll\\ ll Imru li lt' iu h-ractions Ix'lw('l' n acidic d m J.,TS and alhumin a rt' ~t ,IIt'l'llll)' applit'.lhlt· 10 a ll dmg-protetn mteraetious, I)('ari ll ~ in m imi t ht' \-\idt' l)" t1 ifT('ri ll ~ molar l1J1l('t' ulmtitJIIS of rln- vari ous hind ill~ pr oteins in p l'LSIll
uud \"a lp m il' ad d tlu-rapy, ht "(,.UlM' t ll(' M'
Therapevtk ImprKatlon, D isplaeenu-ut inl('r.1(1iolls ill p l.LslIlil ha n ' ht'l"n st ll(lil"tl p rima rily 1/1 dt m . TIlt' pon-uual tlispb' ''t'r is
INl tRACTING DRUGS
CHAPTH 11
ur if displ.ex-mcut IltX'UTh fr om tisSllI" btndmg su es fo r a t1 nl~ wi th a large volume o f di strilmtiun. ; \ 11 e-cunph- of tlu- Fonner situation is rlu- displacement of warfarin from alhumi n h i nd in~ sitt'S by llapm"I'II. Au exampk- of the latn-r sit uation is tlu- displucenu-nt of d i~tlXill Iromttsxtn- hillt li ll~ siks h~ ' quiniduu-. TIleS(;' situa tions arc rl'1atiwly unco mmon. howewr. \ lon ' rmumon is displace-uu-nt . From p tlsllla hilJ(lill).': sill'S, of a dmg: wi th a lergc \u lull1l' of t1islri lllltinll, 11 11"11, 11I"l' tu st, so Iittlt' d m~ resides ill plasma o nly a millimal ehang:1' ill tilt' unbound t1 mg: l,(lIll't'nlralio ll Ilt"l1ITli even when all lilt" d m g: CJIl tilt' p r oteins is t1i.spJal't'(1. as d is('us'wcl ill C ha p. W, D istriliutiou. Fur exampk-, if ti lt· volunu- o f d istrihntion is 100 L am! ~1.}q: of tln- d m g: ill pla.sl1la is hOlilld (f ll n.ol) . then ollly 3% (l IX) X (I fill ' (p t lSlI1a \Ullllllt· )!\" of Illal ill tln- htMly res ides bound in pla.s ma. Ewn if compk-tely t1isplae,'t1. ti ll' small .unoun t aITel"t('t1 \\tlllid ft'tlist rihu'" Ihmug:llolit tilt' res t of tilt' IMIt!y am! stJ \\ll uld only Itlal},rinally inl'n'ltst' th t· unbound Iltltly !'It'ltll and IWlll'(' unbound lUUreutratimrs in phsma ami tissut·, Conceivably. if tl1l' displao -r were Injected mp id ly t,!ltlllg:h , tlu- UlIlIIlI lIld d m g: concoutnuton in pLl\ lIlil wo uld rise appn"<.'iahly, but only mOlllt·lIta rily. 1'It '('all\t· di spla{'('tl d m g: wOlIl
=
Rate of elimination ... Clu ' Cu - Cl , C
\\'1It'1I t1m ~ is infuSt'l1 OIl a constan t mit', It", ;1m! sleady slalt· is adlit·\'I'(1.
Ro
'"
CLu ' Cu... ... Cl ' C...
2
11fl\\,t·\·('f . Sillt'(· u nhlllllill t'!('a nUIl'l', (' .~" Ihat of a ~mlll ·m la rl,· filtt'n '(! d m ~, is IIl1aITI"<.'!('(! by di spla('1 'IIlI'nl, tilt' s.;1I1l(' is Iml' of till' \-011111' of Cu.. . TIlli S, alt llou!?:11 t!i.splal't·lIlt'lll hy i lll' Tt·'l\ i u ~fil inl'n·llst·\ ( 11'
CHAPTIIl 17
2 74
to l ~· n ·lillin4y small. I m 'spl 't1in ' of all~' d TI't1 of displaconwnt. ht An'H ' f . tilt' unbouud coucen t rarion al plateau is IUW(' f t han that
nil' events pn-dicn-d at plateau befon- and an N di spl al't'menl for d m ",rs o f low alJ( l lJ i~h extraction an' Sh(,"11ill Fi~. 17- 2. Slim'l l in Fi ~. 17......1 ,m' th,' tota l and Illlholilid plah',1lI pl;lSlIIlI couceutranons of t ilt" lllltit'p ilt'ptic drug P"("1I~1 oill ill paueuts befon- ami aftN
rt"{'('i\'ing calproic ;lli d, anothe r .mtiepilt·plk
n l(. 17-2. C I... n ~. ;41 p1;4I,'an . i" tl... 1"lal rgl ......1 UlIIM Mll...1 11 1",nn·" lnal:io MlS ( J) - ! ) ,Io.l"'ml 'M' tI...· ....l r.....t io'" r;4l1" " f II..• , lm~
High Extraction
low Extraction
Intravenous
;4,..1 n Md., of ,Iru~ . lmini . lr;41io:",. For ;4 "nlll: uf .."". ""l r....1io.., r;4lin. tliminid....1 hi,.. linl( If.. f ) ....I,....."S II... llJt;d.IM'l lllJt tI... U"IMMU"1. ' ..........Ill natio ..' n~l . J....... " f ll... ",uf" ,/ . hnilli-tr"" IIl. fo'nl"II ,Inll( " f hild> 1"1""lk .-:\l r....1iom r..lio•. c!'·aI"41Il.... a, 1 "'. I,ot;d n m· ,,,'nlr..lio:,u, i.. ,., rr...1,..I I · oIl1" ini'I 1l>i,..I"'I("I..•u II...• ,In'l( iJ ~ n inlr..' ; ,.J,'. 11..· tl"I M.." ...1 n "'· C"l'T ,Ir;41io:",. 1 ...,. iJ •• -..10..:1, Bo'<-..ll...· ,1i",in i".....:1 hit..linl( ,..'(.Tt· "S u...J 1o;''''''1liL.hih ~' " f II..• Ioi,;l' I,' d,·;m.,) "mil:. tI · likt·I,' ,...,In,,,...· of .h. pL.c...." ..·ltl ;d. n-r or;d . h" i"i olr..l io:.n io lit , lo'(.Tt ,......• in lh., lutal ,. ('f'Tltr..lio: 'n ;0,,,1 I,u l.· ,... ,..., '''';0''1:'' in tI...· u"I " 1
Oral
"""".. "lrllti n" . T h.. <1,,1,,111 " ha nl(" d "p"",h " " " -t ·r II rr."<1 on " n.IIIit""'-aiWJi!ityor . J'"":k>l"i""I'"I
"" 1(. 17-3. n ..· ' '''pn>it· "",*I--I'I"''''~1''in 1""·......1 ...,,, i''''.....'" .1i.pt.....·" ......1.." Iy. AltI"",,;I, I,la." ml l'" ot.·in IJi",II"1(of pI"''''~1ui'' lo ''' C'R'll...,,1wl....n ....liu", _>d . pT'' '"Io' io ...1",;nl-kn..:1 d'I'I"'io:.." II, tu a ~ "'P of i"" tif'nh ~lilt.ili7....1'''' p1"'·fl}1uin. "'111. ;0 " "Sult;o"1 f;oll in till' ' 1o·;oJ~·.OI ;4'(' p l...."';o plll'll~1 "l n ...",.,,'n lrilli.m. ti,.."" "'.... 110 \l, I..I;o"ti;o1 d lillll(" ill tI... n " I...",,,,1 pI"'n~1'Ji ', ,,,,,,,,,,·nl natio .., ("olt...). n ....., ' >!"'·n -..J io:..." ;on ' ."""i" ..,,1 wil h II ,li 'p l""'' ''II''' ''1 i" l.. rlK-ti"" of pI"'''~1' Ji'' I." _-alpl'loK' "",;d . s .ot" thaI I...• '"'W''''' " f p1"'"~1' Jin "i,pL..~n",·n' ,1o.1",,,,I. '1Il II... .10.... flf .. .. ,Ii"", ,-alpn ""I"'. II..., 2S l"'hr "l.ool;dJilin .,) .1<.1 pI"'"o ~t'Ji n . I I ""..-it..,,1 \JIIIO mil: ....It"m _"'p"~lh' 1"" 1' .... ~.: 9 " '('(-it...,) II 13.'it).. ml( .L.i~. .......; ",tot! oon... .. " ..'i\~..:1 -Ill ",Ml. IT;o~.'Tl [rnsn I...Jth 11'1(1"" '''0 (I mWl· ~1 ..lhfln . lUI., C r..,.,..r . J.A.. \\l l1ioa"'''' IIl. P,D., S'" '' ..l/y. K,A.; \'alpruk' ..* 1in rpiJ.,..y Chll k-..l" ,...1pl...r. tIl"",~"'>w<-..I ..rr,,,-to. An". S .."n>!.• 3 21)..25. I Y';'~.l
or
-
C
~ S
18
0
C
o
C
o
N- 25
Total
16
~
0 .~
"
w-n 14
Total
~
0
0
~
0
'-' 12 ~
"0
s:. ~ ~
10
~
00
~
~
2
0
N ,,,"-' =v='
Unbound
Unbound
Unbound
0
900
1350
D D D
CHAPTfR 17
Di"IHJllil io n lUnd i n, 111l" subv-qu e-nt poi nt s SUIll Ill'II;7.t' those.' made in C hap te rs 10 to 12. Ht '(.'U u ~, dt'am m.'(' of a lln lg with a high extraction rdtiu is IInafTl"(:h"(l by di.~plan_' ment , til(' hal f-lift" (:hangl"S with volunu- of d isl ribution . I II contrast . for a d n l,!!; of low 1" t ract jou, b("('au st" uubouud clenrancc-, CI ." . dIM.... 1101 dmll!J;c·, hillf-life either n-mainv 1"(11I staut [wlu-n \'" does not d l'lII ~t' ) o r sho rte lls (if \ '" tlt'l:n 'll.SI'S) wi th di sp lill'('JTlt'UI From pta~lIl a prote-ins, pla1Cma COllct' lIl ra l io ll- Tim e Profile , Altho\l ~h then- an' many l'M ,ssihl e ("(,mh iualions o f r-vents, only nne rouunon situut um is ("(msidt·f("(I. 111 this (';l.S(' (F ig . li-l ) tilt' di sp la('('r, wh ich I..l.~ a 111ll ~N '1IIl thau thut of till' t1m~, is mlllt'tllc i till' f(W lnt 'n of
Displacer Drug 100 1.0
~
§.
50
0.5
20
0.2
10
0.1
5
0.05
2
0.02
1
0.01
Total Oruo ~_ _ -
, ,,, ,,
c
~
" ~
u
c 0 u
, ,,, ,
~
E
~
"
c,
"
0
1234567 Time (halt-livesof drsptacen
5
Drug
'7
Displacer inf"... ~ 1. 11.,· .."1••,,..1<..t .. ~'''tr.o'.", (" .I",) nf .. ,In'lit ,,;11. a 10",tI, .. 10-" '1{ half_lif" . n·I.1t,,,, In 110.· dn ,lt. ;~ rili...r l"f, n ... (-ha"I{<' in I'Jl..II>la' llla ,Inl): (,o1I.., · " ' .... h.1I, n·H,..1~ tlw ,10' 1,1.1""""'1 '1, . -i.lt.
17--1.
\\l ,,·"'~ "'-tanl l~'
... ",ai n '! \trt"" llr
", ...-hanl:<..1if It ,Io'l'Lot..-.
t-,;IT;oo.1M", rollin 1or .. ;1", 1 r-~1l .
".
CHAPTER 17
INTE ~CTlNG ~S
IlliboUlld ('1 J1l('('nl r.ttio ll ll1i~"t ocvur if th e kim-t ics of 11ll' d m~. rather than that of tilt' t1isp lal'(·r . luul lx-eu th t· slowc'r. 110\\,("'1'(' ( , thi s situation is I'd.din-I)' 11Il( ·OIll IllIll I . In till' (',l-W just diSl-11.\S('t1. 110 dmll ~l' ill l'lTt"(1 a ndIn-no - In tlu- d OSll.l:l· rt'¢lnt'n of l ilt' t1m ~ is ;lnti dp;llt'tl e-va-n I l.oll ~h d ispl;ll'l'llwnl 11,,,-\ oc ou rn -d. Indt'('tl . if only « 'S p U Il s(' wenuuuutorex], displaceuu-nt \\1I111d Ilo t !MH' !lt'('1l slIspt '<.1c'tl.
DIMINISHID UNBOUND CIIARANCI 1\ n -dncnou ill lillhllllmi ck-umnce is 1"01('1111;\11)' tln- mo st dal\~t'rt m s 1~1)( ' lIf dm~ interne-
uou. T Ilt' unbound dm~ conce-ut ra nou <';t11 111('11
n sc 10 a toxicle-ve], unless a ll at ljusluwlIl
nuuh-. <:OIl'\('( jll(·lItly. it is (·~trt·"l('lr impo rtant to he aliI,· to i
li lt' nmjor ('auS(' o f n-dnc cdunbound ch-arunce.
A (ase Study Sllll\t· patient s n '('( 'i\il\~ t1lt·nplayllint· dt ,\·(·lnp mUIS('a wln-n euocn-in, a n a l1!i·inft'<.'fh·(' qum(Jlim·. is "ddt'l l 10 li lt' Iht'(lp lJyllim' r t'WllIt·n . TI I(' mlllst' a is a\s(K:ia h"tl with uu t'! t"'111t'(! ('Ull('(' IlIr; I!it lll tlf Illt,(lp l'yllim ' (·il.lIS('(l lly euoxaci n illhi hit ill~ tilt' nu-tal jolisru of t1l1,(lphy'l[i 11(' .
'2
Enoxacin Slopped
,,~
>'E
,•
8
~ ~~
0
~
~
0
-
ro~ '" E :0 ~u ~
ro
-
0
~ '-'
,
Started
~ -
•
• •••••
•
•
• 4
Theophylline Stopped
• •
•••
••
,
•• • •
0 60
' 20
' 80
240
300
360
Hours FIll;. 1i-.5. E""'.... 111 i" I'il' ih t1 1< ~, >I I\II; 'I< ' 1·limin.,I1I' "f •.,1< .....";,, """t 1"1'01' 11<~'n . " Ili<;'·"1 In ",,,rnl ,,;" "1'1' ·d ,,I.II· int.il,;I" m f"r .....", . li",.. . 0111<·...1,,·. II..· n1"", "r 111<.. opI ,~· lIi .,, · In II..· I,n " ,·""..." 1" """.·"Ir;ll(.", ", ,Io llu-.. · In'n ,," ,,·h . 11< "to-r. 1"'; 111( " " l<-nn;''''II I,:,' ti l<' ' I< ,n nal " alf·lif,· IIf 1 1 "'I 'I>I,~ lI"M" " .. h, (l 1 "~'I>I ,~ l h, ..·; I "'WI. - ."i.~ ~ \ I ) " \I , ..lifi..l l'n H" R,'IO:t·. \I e .. So""'''I<''' . \\"It " So..I",..... .'I.,J . \\".·l h ,,~ 1' ( ;.. K,.. ,I" J R . ."..1 \\".'Io:,,,·r. r G.: 11... t11<"'f>l~lIir"'''''I<>:\ati'' i"" ·..",1;',,,, 11 e h.. n~ .. ill II..· ,1i'1".;I"'" "r 11..~ , >I,~ III1" · ..,,,I,h " ...Iall< >l i" ... . Iuri,,~ i" "'n " il"''' l ...h" i";.I....I" 'n or •.,1<...." ;,,, e lm. 11", n ",... >I. l1M·T.. ~Ii A ~()- I ~"'. I~!l l
CHAP1H 17
lN1[RACTING
DRtX:>S
217
1111' d ra m,ltie riw ill t ilt' trull ~h plasma concentration of 1!l('oph,.lIill(' wll('l1 ('110'1(,'1111 is ad d('{1to li lt' rt'J!illlell a nd t ill' n-tum 10 tilt' pre-euoxaci n vaha- ",,11t'1I t'lI l1 xactn is \\11Iulra\ \l1 a rt' iIIustrah'{l in F i!!:. Ii ...'). :\oti('( ' that it takes appm ximal(·I)· 4 AI) '!' o f enoxacin admtn istrutiou for 111(,('p hy llillt· concentration to rise to the new pla teau and a similar till\{' for it 10 return to t ilt' pl"(·-(·lJoxaciu vahu- a fkr r-noxacin is ....-ithdru....lI. :\ uum- quant itative pictun- of tilt' events Illay lx- ~ai ll('{ 1 Frorn twu equations. 0 111'. prt'\111Ilsl) ' t'\;\millf,1( E ll' S. C ha p . i J, defill("!i Ih t, a\'l'rd!!:t· concentration of dOl!!: at plateau
c
.<~
•
F - Dose
cr . t
3
TIll' u tl ll' r c'flua tio ll d d il1f's IIIl' III " \" (a llll lo IlW' r) hal f·lif(' of th t'f'p h )'Uillt· ( ' Ir.i!~n"iI",.. t) in n-lation I" tln- no rmal !Ialf-lif(' (' II2.•~ ...... .J)' 4 wlll' rt' CI.....","" aud Cl' lnl"J.".., an- the clearance s o f th ('{)phyllill(, in the al)S('!ll"l' and p n 's, n f tl u- inh ih itor. rt·"llt'l.·!i\'d)·, Equation 4 foll ows From t he equation k "" Cl./\' and fr om till ' know!e dgt, that r-noxacin does no t alTl'("t tilt' \"(,11I1I1t' of d istrihutinll of t ll(>(lphylline , a dmg only w('ilkly hOllnd ill plasma and tissue. 1111' hal f-lifl' o f t1wophyllillt , ill th e ahst 'II{'(' o f ('110\;\<111 is SB IJr . ('st illlah'ti from t!l(· d('d i ll i ll~ couce-utrution wlu-n th ('flpl. yllin{·mlminislmtion is stop !lt't l (d ay 13). As expected, \\1111 \111'1 1 a sho rt h.tIf.lifl', thl· plate-au coucentrution (C ........ I, (Thyllillt' 1"('J!illw n . Euoxacin is mpidly ab..orbed and illllll('{liah·ly lnhll uts Iht >(lp lJyllilll' lll(·ta lll ilislll wln-n admiutsten-d u n lilt' fifth day into Ihl' t h(>(lphyllirlt' n-giml'I\, \ Vil h conttnual administmtiu u o f tlu- sa llll' t1ns a!!:I' n.~llIt'n o f tllc'tlph yllil\{·. its plasma conce nt ration rises to a new platr-au. a ppm\i lllat t'!~· H IllWL. t1t' te n n ill{'t1 h)' t ilt' I W\\'. am] lower, clea rance \1.1\1(' (CI'.nl,J..,..t ). A{'l'(mlillgly. by n ·f(·f('Ill't· 10 Ell. 3. ( '11(,( '
C...aY• . -moI
C"'aY.;"lIob;~
5
and on s n hst i t u ti n~ 4 lIIWI. a mi ~J lllWL for C...",..... ..-.I and C ..... , .I..I,II>it. .' , O il(' ohtams Cl ', ~j,Jn'(lpla)·ltillt' h)' 56%. Thi s calculation is h;l"t'tl 011 rhe a ssumption that th e bioavailability of theophyllmc. whicb is usuallv well «I."o rl)('(t is IllI.tlT{"{·!t"(! bv cnoxacin. 1111' ;It·W half-li ft· o f tht'flphyllint ' in tl l(' prcst'n{"(' o f till' inhib ito r can now lx- {'akulat('{1 hy apprnpriatl'ly s ll hs lit ll l i n~ tutu El l' -1; it is 22 hr (8.1; L X 1111,44 ). 111is lm l ~{' r h;tIf· lif(· ('spl a ins w hy it lakt,s 4 day~ . rutlu-r than t lu- usual 2. 10 reach the I \l'W plateau. It is also W llsistt-n l wi t h tilt' o h"t'I"\'alion t ha i 1111' plas lIla coueeutm tum o f l llt'tip hyllill{' (6.5 mgtL ) mid w;!y llf'twc't'1l ti ll' p revious and plateeus occurs I da y afiN atl min ish' rinl:( (·llfl:l:ad n. 11\1' slow return of the ph~lIla thoophyillnc ('fJll('('n tmt io n to tln- pn--e-noxacin value U ti wi t hdrawal o f enox.u-iu re ma ins til Ill' exphuned. A h hull~1a withdrawn. tln- conce-nt ration uf ('IlO\;Il'ill ill ph'illla !It·rsi.s h al O!i Slil u f lllt>(lplly llilll' fllr a {1111sit!e mh lt' pt'ri()(1o fti llit' . As sll{k til t' ha lf-lift' of t h(>(lp hyllill(·. w hid l ('fmt m ls t ill' rdum o f th(,{lp hyllilJl' to ils pn'-(' Iloxad n {"llll('('nlr.llion. rt' lltai llS t'1(O _ \':111"11 fo r Sll lll(' t illlt'. H ad illhi bitiull ('(·..."t"ll illlltlt'{liatt'!y Ullt lll \\;t1l{lnl\\;lI ~ (·llO\adn. t ilt' half-lift' o f Ihl 'f'phyllillt. wo uld ha\'t' f('\'l'rt('l1 had; til its l'(mlrol \'a lut'. k.S hr. :lIld th{' rt't um of Ilu>( Jp hyllim ' {1l!J{'('nlraliolJ til tl lf.' prt'-('uoxadll \'lIh lt' \\"fluld ha\''l' Ill't' ll mudl q uit l t' r.
Ill""
lNlERACTING DruGS
Cl1AMf l! 17
AGradedlHeet Til l' ];L~ I stat euu-nt ru-eds St JIIl l ' amplification. TIll' illh ihil ioll o f Ilwophyllim' hy enoxacin is 1I0t all
6
Km
d m~ conceutranon , CIl , is \\"1·11 "dow till' \l idl;l...Jis-!\!t'1lft'1I 1'{ llIstanl, Kill . O r. ('\ pn'sSt'C 1 ill I...rllls of IIl1l NJIlml clearuucc associated \\i th m(·taho litt· formation ,
,,1."'11 the- unbound C l.llf ·
7
Role o f metcbcbte formotion = CLu/ ' Cu = fm · CLu . Cu
,,111.'0' 1m is till'
Irucnou of thr- doS(' uf ( ! nI ~ th
A
B
150
4
.......,..•..~ -,
? loo ~
\"4
i
0. §.
•••••lI.
'-' ~
i
o
o
12
24
36
48
Hours
50
o
o
100
200
300
400
Dose (mg)
li""
!'·l l( . 17-6. n ..• i" l,ih;ti.." ,of t l " ~ 'I"'l\lI i' ..· ..linm loy "Ill_ i n lO!fr t. ~I . ..., ......t.·lln~ 1 ,~' tl..· p n>ltl lll(;olIM'" i" l..,If.lill· " f . t.~·li, ..· ..f pI..., ,,... tl.. ~opI,~-tlill.·,...K ntr...t it"' (Al ..., ..1 il .......· in ,.\ t 'C: lll) ", I,,·n ... 2t.I. ," ll..t.....• .. r tI..~ 'I'I,~ lJ i ' ..· j, ...llI1 i" j, lt·.. ~ 1 ale" ..• {_I ;,,, ..I .I" " " !f j .. Lo~ "" ""'no "f 25' 1I11f (0). H.1.1l1!i: 1"'1. .uKI 4t.I.",ll. (lI.l .·,..,......i " !Q" '" '''' '1)' 12 I" . 1>,,1... ....... II..· " ..·... n. "f .. 0" I 'jo~1 ' (I "'WI. - .'L5 1ol .\ I ). ( I)",... fn >nl R,"I«'·. M.e .. S" I0 ", ..", . W.R " ~Ima" ..' .J .. W.·llm\f. 1',1:., T""th..k,·r. !i l).. ...nd \\·~" ·r. J C:.: n ..· 1I..~ 'I>h~'1Ii1"· .. ·1.. .......,1l i" k r... tioM" I. EfT t " f .·,..,uti" , I.",. 0;7<'..Tl II.... 'I,h~·lIi'"· ,Ii' p"'i lio ,n , eli n . 1'I,an n'It..I. n "'r" ..l :.s7U--.Yt'i . 11M.)
27.
INTf iACTIN G DlIUGS
O W'TH 17
Role of metabol ite Iormetion =
Clllf ' ClI
1 + ClI/K,
8
when- e u, Is till' u nho llnd conee ntrution of lilt' inhi bitor lind h, is till' inhibit ion e usstau t . /Q\'t'n h)' the unbound couceut rattou of inhih ilo r that dl'('n 'a.<;t's CLuJ by tw"fold. C ll'arly, Iht" !owt'r the h " th e mo re POk llt is an Inhtl nto r. T wu main conclusions ma~' 1M' d r awn fmlll Ell . S. Fi rst , thr- dcgn-e of inhihition of a part icular pn then- art' mult lph- pathwa j-s. E\,{'II al the hi~ht's l dost·,
so
t' no~ldll is o llly ah le 10 reduce lilt' (tulal) dt'a m nl1' of t1lt'o pltyllillt' hy app m\imat d y "mfold \\i d l U t"(IrT\'slx mdi ng dOllhl i ll~ of d ll"()pllylliltt' half-lift'. l1woph)'lIint' is t,lilllillalt'll hy dt·lIIetll )'I;ltioll. ri ll~ oxidation. and n-nal cxcret tou. E\idt'nlly. eunxaci n inh ihils u nly 'ilIIllI'
n f tllt'st· p athways. Tilt' antidepres san t d t'sip r.Ullillt' , Ilw ta1lo1i;r.('(1 h)' the <')1OC'h nnJl(' 1'~ .5() t' nz:"'Jl(', C YI"'2 D6 (st·t· Chap. 13 . ( rl,'uetil"S ) 10 form :2. hytl mxytiesiprd lllille , is anothe-r examp le , Qutnldrne. a IXI!t'1l1 Inhtlutor o f C YP'2D6, t·ITel 1iwly co ne...-rt s exte nsive nn-tabol tzers of d eaipra tniue, in whom this path way is a major nne, 10 IXIIX metabohzers. with a pmnouneed reduct ion in d eanUl{1' of appmxillmlt'ly fOllrfoltl ant i {,( IrT\'lip0lJ{ li n ~ prolon~a ticm ill llalf·lift ,. In such caws. the clmk-al conseq uonces of an interact ion dC'l'It'nds o n tln- n ·lali\,e {'tm trilm tions o f d nt~ an d 1llC'laholitt· to efli t';ll")' alit! toxicity. \\'ilh desi p rumim-, til t' dOM' ill exte nsive lIlt' taho li/.l.'r.; sho uld ht, red uced to avold toxicity. if quinidun- is ('t)lldminislt,rt'tl. As Ill i ~ht Ill' cqx-ct cd. llu iniclim' h iL~ liUIt' t'lTc't1 nn tln- pha n na{,(lkillt'lks o f desipranun « in th e alrea dy poor C Yl"'2 D6 nu-tabolizer pht'llot )llt" bt'l"lUlSf' the alTc'(.'lt'll p
AMultifoceted Interaction Although lilt' antt-iutlu mmatory dmg p l\('nyllmt;wmc' is 110 longC'f wich-ly used . its interaction with warfari n is \\'t,II-du(·UllWlllt"(1. 111l' int e-raction has {"lIU!\('11 st'rin us hlc"t'l ling 1'1'i!\()(!t-'s. Warfarin is laiglaly IXlIInd in plasma 10 albumin. PIlC'nylh util1'JlIlt-'. c!t'\ u id o f inlat'n'n l anticoa gulant act ivity, di sp lac'('s warfa rin . CIIll!\('(IIIt·nlly.
,to
O W l H 17
AI Clli<. point. Ih t' ("'I'nb ill p l
ami w:.uf a rill it; fully hill;I\-ailahlt·. C l .ll must ha"l ' (k"lTt·iL"t.'l1. W a rfa rin i\ alllKJ"lt t·WIIL\i\l·I, · IIlt"tah uluJ'l! in dK" liw r In t'ifh t'r "1 ~a k1, · itC:'( i\,' o r inalti\,· llM·f;lhulih.... 11111\. a !tM" r \..ullt" for C I...fl illll)I M~ a dt '(Tt'a...• in tiM' a hi lit,· o f Iht· liw r to IIIt·tdhufi7~ · wa rfa riu . ;\ n'I~ ... i'i nf "' ''\'t"r.tl n""tal lll ll i h~ o f warfilrin in llllllh pk\lI ld a lKlurilM'" \IIIN "IIUt'IlII, (''fInfin llt'l l d ldt. illtlt"t'l l. pI M'n,1IMlhlJlllll' inhibi ts warfarin dimin.ahnn. a ud it i\ th i' inhihi tHIIl au(l llut (li\plal"f"lrwnt fh.d sccoents for 11K" d illie'.tl p Kt ll A.·. 11 "," illftoraltiull ht 'h\' 'l'1I pIK'II,fhulaznn e and warfari n is ("\''11 IIJUA.· (l.llll p!t"ll. than purIra' l 'll ah u\(·. GIIlIIIM- rdal warfarin b it racemate. d ldt h . a 50:5() mixtu re of R( + )- ami S( - )-"-drfa';ll.• mtl tilt· S( - ) Isome r is fiw lillK~ murt" al ti", t han fltt' R( + H ~ 'IIII·r. N tt'n , lh llla7u llC' p rimarily inhihi ts tIM'" fo n liOltiulI of 7. (S )-h, u ml;) warfari n. tl tt· ll101jor IItt1al 1llllih' uf Il.t· lIIu tt · 'K'fi\l · i-.c 'IIM·r. 11 M' les ...nll is d t'a t': () m~ inh'ral'f HMllO call ht · l''Ump Jt.,; ca r eful IIIN ·n ' ltiulI\ an' n"lillin'li to lIurJ.\,·IIIK" (ali s.
e
tlC· 17- 7. \ \ ';&r{M1n--phrft, D"II...... .. ;nlrn.1,nn \ ...1"..1 " ..~ ... I lll '''l .... uf.."n onTh. ........ cla:-' .. ,,1 11M) ml 1"...." 11,,,1,.."",... .h...... Innn it '~' un .L",.. 11III 2.2..\ ' .1..• r1. ..~ n" 'I"""""·"'''''PT1u~u..n " ...... 1.""..I "lI.rf~ nn .....' t1,-rt- ~ .. I. ......1 tlwo rL<-"'" 'IO';arl.."n '~" " ...n. r.ot" ", f..lI, n.·.....;&1......1..1."• • '" In , I... " " I. "" .. I "·~rl..",, ,1,," ,,1tr1" "'~ D"'I............ 1.
"'''''''rod"", 1,,,1'10....."1"1".,,,,, III .. ~f..n" .·hlni"..·
tIl '"~ ( I'I,, · ,,~ II" 'I"" " "·,
1 ,, ~1 . • .1.2 .. \1 ; .. '. uf
'n"'..,,;" \"")(
·C
0.04
.......
'"~ 0.03 ~
e
~
e
~
=>
E.
0.02
0
• •
0
~ u
e
0 0
0
o
•••••
0
0
e
~ ~
0
0
•
·C
" 3: ~
0
0.01 0 4
e
••••
000
~
0
0
0
••o •
0 0
•
o~
2
0
0
'-' ~ E
0
e
0 120
3
80
~
~
0
~
0
~
~
-s, e
=
0
•
40
0
• 0 0 00 .
~
c,
.....
0
0 0
0
0
0 0
10
20 Days
Warfarin Phenylbutazone
30
40
CHAPTE ~
211
17
Other (ouses of Reduced C1eorOlice Inh ih ilioll of metabolism I1(I('nt 0 11 IlIl' pllL'ima conceutmuon of propranolol.
Beneficiallnteroctions Pt'n id llin- p rnIJt'lIt'('id com hiuatkm t h(' rJ.p~' is an example of Ih(' sUl"l'('SsfuluSt, (If a dr ug interaction. Both of till'se acidic d rugs arc n -nally secreted by an anionic tr,mspo r! S~"!i l e m . Pmbe-m-cid t,(llllpd iliwly illilihii s the renal secretion of penicillin tlwn'hy suh sta ntially n 'l illdll ~ Its n 'na l deanmct', the major compon ent of total d t'amll('('. CllllSt'iplt'lllly, in the (In 'St'llt'(' of prnIJt'llt'l:itl, lI i ~IIt'r tha n usual pla.s ma coucentrarions of pcrnctlhn an' achieved full(J\\i n~ a nonnal dOS
ElEVATED UNBOUND ClIARANCI dnl~ can 1M.' iU(·n "L'>t'l! in numerous \lllp ; . R ilisi ll ~ urine pll hy W\;u!-: ill'l'laJ'.ulam idl' or sodium bicarbonate increases the renul clearance uf sali(·,.Ii('
TIlt' un lltlllm] dt"tr.lI\t'(, of a
Administe red with Cilastatin
80
HJC,. 11-Ji.
l'Il'a" -S lh.,
Cila."'a lin marl<.",l1~· ill' uri na l)-' t'\(...-tit•• of tilt'
,m l il,i" l it' im ip<'Ilt'lll loy il1 h lh i\i " lt IlM, tlt'h~tl n'P'l>l itL..,,-· in til(' ~itlr ..-:..."'I...l'i l>l<. ito 1t .. -ta.l.~i.m . Th· llri n ;H~' n-cov.. r~· u f umpenr-m io
f".
••
1.\.. I.~ " 1<.... ad m ini\t .. n ",1 alt.", ( "t,,:~) anti 10 _ !:,11M"r " il l. a n 1.\'. l . ~ ", of 51_' 11111: .... ...11 afk r a ."jI j(). 11 'R
Imipenem Alone
d lll'llili n ( (~ ,l "rl. (Rt,tl.a..." fro m :""r1 ~ S R...... I<"'hJl:. " .. BjI\n ,,~ . 8 .• H u r m an , 1.. ..... . F,'rb l" , F .•
lI ulM·' . J.I... J"'l<'o. K II . " ;l.1I1I". r .M.. ..:,J u.n. I·S., Kn'I'P. II., M,-i•. in,.," , ),1... ...... ;1.1,,1 s"I."·I..tf. J(:,: UrilW)'
o
Tl'l''''l'ry of
l" it'naHl~,in
.'\ . fnTln i mit~ ~1
(M" O!"7 ) "-, ;l.ff''(1.",1
I.)' .. -.lrni ni..tr.tit.l uf
s·r..nni mi ·
,J.~~ lhit'n;l."'~'in .1..t,~. l n 'l"Tot;,Ia,, ·
i nhi h it " u . .... llti"l k r oh . ." II:,' nt . Cl.'mt ol l..'r.. Z1 ::!U l-,l U7 , 1""'1.)
212
CHAPltR 17
ad d and otlw r ad(l~ who'i(' n-nul d ear-lllct' is p H sensitive. Gi\ing ammonium <:illo nt l.> or ascorbic add to make 11.(' urine mo re ad tlic tncn-ec....·l; til(" renal ck-aram x- Hf pll ' S('lISilh l ' I "l~ i<: drugs. SOllie drugs Increase tht· lIleta ho lic d t·:lr.IlIl'l' of otlwr 11m"'1\;. TIlt')' dn so most l') IIII1l(ml~' hy ind ud llg tilt' dnl ~- Il l('l a"oli:d ng e nzynu-s. hut tilt')" lIIay also ad i\"alt' ('1lZ)11WS or n -tanl ('nZ)ll ll' degrmbtinll. (k1.1L"i o lia lly . Iikt· glu(:agoll . tIll''' Incn-aw hl'l );llil' hloc)(llIow and t1wreby iucrvaw the hepatic clearance or drugs thai ure highly ext rurted h~' lht' liver. (( illl ,ti<: l'C IlIS('C llIl'IIn's of an iUert'iL'i{"(lml'taholit, <:!t';tr.uw(' WN t ' d isclls.... -d ill C haps. 11
am i 12. n i l' im pliedtiollS u f tlu-sc dmllges Oil dO~lgt' requirr-ments nnd Ihe- <...'ents that follow Iht' itd d itiull or ui thdmwa l o f dm j{ l"a us i ll~ tht' alh 'n-faJ. a dnS
II
. ·IK. 11- 9. " 1" 'n ;< 1),tIM'nl «I"hili7t..1 '''' Un' lt A
;aI,," n.. , ·iw. Unlit H. a elm): tlwl inc:n-..,,~ tiM'l·k~;m lt A i. nul " . I'K....I 10 Ih. ' pn~i..tJ. ""t., "t...n 1",i",,,,,,I;..,, " f 1>"'1: II i. ,,''1 '1....1. :-.;,,,.. 11...1 ti M' lin In n·....... I'Lt .·;tU i~ k ~, In II.., pn'S<·.K..•. II"", in l!..•; " f U m-.: .\. (Cit..•
''''1'"""..
0 1 23 4 0 2 3 4 5 Druo A + DruO B DrugAAlone Time (hall-lives)
Dosing
Rate ~ J, ; -- - - - - - ~~ r - - -- - - - - -1 01
Drug A
o
Drug B
CHAPTE ~
17
INTERACTING
oacs
En z:,"llw induct ion \\~LS men ttoru-d as tll(' prime cause of increased metabolic d earunre. lI o\\'I'\ t"r, u d liUl~(' in dl'arall(o'(' is an indin"<.1 measure of the effect o f an ind \l('('r; til(' din-ct ('fT("<.1 i s all Increase ill the synthesis mho' of the drug-llIt"tahoIi7jn~ enz:,°llle. A(:m n li n~ly, there is " ck-lay h('tWI'C1l the di rect e ffect and its refll"<.1 io n in the IIlt'iL\lIrt'(l rt"Splm ~ ' , TIlliS, (,\'('n if tilt' pJ.L\ IllU concentru t jon o f tilt' Inducer \\'('n' at taillt'(l insta ntly ami the n maint ainer] constantly, th e clea rance of the afT("<.1 t'(! d rug would illtTl',IW \\i tl! tiuu- ll.\ tilt' ('I17.)""l' 1(" ·t,1 riws from 011(' plah 'iUl \111Ut' to anot her. Similarly_ tln-n - is a d elay in tilt' decrease in clearance of the afTe<.1('(! dru g on removtng till' Iuducer. 1111' tum- (l P] a~' d('I)('I\(Is, likt, ot her sys te ms in the hotly, on thl' kiuet ics o f the d rugs and tilt' ('IIz:,"111' tnvolvcd . \\1lt'1l elimination of enz:,'ll1e is the slowest p n K"t'ss, then cha nges ill d('anllll'(' of till' drug llIa~' contnuu- tn O('t11r (" ·('U tlIOU)!:!J the coucentra tm n of the inducer is rL'latin ,ly ccustan t. \\111'11 , howt" O t'r, elimination o f tilt' induce r is slow , changes in tilt' roucentratiou of Inducer art' t11('11 n 'I1I"11('(1almost instantaneo usly hy changes in tilt' amount of ('n7)"llt· and h('nl'(' d ear.lll('(' of tilt' afTl"CtN I d rug. Thi s last possibihty may exp lain the effect o f plu-noharhitul on the temporal chun ges ill till' plasma conce nt ration o f dicumarol and p roth rombin time. a measun-o f its ,lTl t it,( );I~u la ll t efTe<.1 , in a patient re<."t'i\ill ~ dicumarol ch rou ieally (F ig. I'-JU). Both tIll' fall ill the concentration and efTe<.1 o f this tlnl g follO\\;n ~ plll'Iloharbital treatment liav(' hl"l'n att rihuh"ll to the barbiturate ind ud ng the t'n7)111l'S n 'spo llsihl(' for d il'un mrnl llwtaholism. It takes app roxilllutely 3 to" weeks for the plasma dicumaml bot h to fall to a mhumum du ring phe-nobarbi tal admmistratiou and to n-t urn to the p rdlilrbitu rate value after phenobarbital is disco ntinued . Pln-noba rlntal (t l/ Z of .. days) al.\o takes app mximatl'ly the same peri od of time to reach a plateau in the hod y and to he d illlinah -cl. l1 UlS, the ohst' l"vations a n' 1,()lllpat ible \\ith the hypothesis that till' indlll"l"ll ('1I0 °IllI' spte m responds rdati\"t'ly rApidly to changes in plasma phenobarbital couce ut ration . Fur a furt llt'r dist:'ussioll of tlJ(' kinetic llSpt"l.1s of tnducttou , 'it'(' C hap. 2.1, Turnover Concepts.
40
40
., u
~
0
30 ~
.2~
E 20 ;: ~
zs E
10 Phenobarbital
/
e
~
'5 ~
c,
'-.. 0
o
30
60
90
120 Days
150
180
210
Flit. 17- 10. ," " mini' tmti" " "f ph"'H~rhi'a1 (fi(l mil: daily) 10 it palil'lll n'O';' ;n ll: ,fk-,,,naml mnlfliodl~" ( ~ mK n..l"n .. Ih. , pl..., ma '''H'''''ntraliou " f tI... aUlk..,••!t" L.ul ( e ) "",I p",' lln>mhin ti ",.· (OJ, it " ......' u"" " f its ,·ff...1 '01 ' tiM' " MK..'utralil", "r tI..· "Hamill ":r
214
111l" data ill fi~. 17- 10 sUAAt'sl that prothrombin tunc Illay 1"-· maint ained at lilt" p rt·· ba rbit urate value by rdisillF; the dose o f d icu mam l duriuF; ph enoharhital aduuuistration. All increase-d risk arises , however. if th e dose of ant iC'tKtj..".Ilant is not reduo-d when phcnobarhilal is dlscontmued. 111l" plasma dicumarol conceutration 11\('11 rises insidiously. ;L' phenob ar bital is slowl)' elim inated, and may ~o unnoticed for seve ral weeks aftN di st'o lltilluin,i1; l lit· barbiturate until. perhaps. a hemorrhagic crisis occurs.
STUDY PROBLEMS (Answers 10 Study Proble ms ore in Appe ndix 11.) I. Bnefly comme nt 0 11 the
aC(:uroll,' of the follO\\i ng statements. a. Drug Interactions a rc o fte n de tec t ed when an interal1ing dmg is Inlnan-d or with-
drawn. h. Displacement of ()m~ A by D m~ B occurs when llit, mola r concent ranou of Drug H approaches th at of the protein that hind!' Dmg A. C, Displacement tnteracttons are g('lwmlly not tllt'rrJl'nJtlc dnl f!, j,.t,'rtletiOlU. d. of the various rncchamsms of drug intcructkm, luhlbttiou of metabolism ill of primiU)' therapeutic important't' . e. Dm g interactions art' ~(' nemll)" WlI
5
~
0
4
~
c
~
u
~-
8a, oE 2 -
0
3
2
~
E ~
f£
1
0 0
6
12 Hours
J"IJt. 17- Jl .
18
24
( HAPTff/ 17
2IS
40
o +--~---,-----,---,
o
12
24
36
48
Hours
3. Chlo nli.v~ 'PI\itlt ·. a Ill'Il/AltliillAl)int>, W n·d 10 ~i\ I...alt l l~' \ul ll ll h't' ~ (-1.3 1Il~. l .v, ho lu\ ) ill l·rn\\O\ "(·r fil..'ihio ll alone or 0 11 th~· fifth day of a tLily -IfIO"ITI~ ~ In\(' of !wtUlUlI 'W III·, an allliflln~al agent . For tl R' pu.-post· of th is probk-ru. tilt" d nl~ ha.\ onee unp arnneut 1Il()lld charact eri stics . ~I l'an \'1iIIlt"S of C(o ) and t II! for dllonliil.7A'Jlfnjtlt. an' ..1.11\\11 ill Tahlc' 17-1.
r..... 17..... 20 230
20 43 '
~ ""'""""' '"a...,..,. ..... W I/dr:l
a. I . Prr-pan- 01 .. t' lIliloKaritlllllil' plot o f lIlt" mean (1I1ll'1 'lltmtio ll-lilllt' p mfill'" of (·!.Iurtli;VA'IXI\idt, in till" pn 'S!'lll'1 ' and absence o f keroconazole. 1.111)('1 hott. llW" and itlt'ltli ~\' !loth l·..rn·... 2. COll1plt·tt, tlu- fflll( l\\i ll~ !;11l1" . \ \'itllI1111 Kctoconazoh\\'ill. Ketoc onaz oh\ '( I.)
C I . (l A Ir) h. (;i\ 'I·1I tlMt ('hlonlia7A'!xnitlt- is eilmiuated by luotrau..fu rruatiou in tin: hvr-r, what p"rsilll f)~;l· nu-chan i..m (s) (Qu, f". f " T' Cl...... ) is reslxlII..i bl~' for tilt" inlt·r.K1illll of
l l·tO(1millt ,II' \\i ll. dllnnliillA.lxldde ? J lIsti f~' a ll)' aasum prious thai ) UII 1II;I" t ". -I, 111t" data ill Tablt , 17-5 silo\\" tt.(· time COUnt· of the concenrnmon of I ht>( lflh~11i1li' t1 l1 lin~ treatment with all oral 30U-IllF: sustamed-n -k-asc dosa~~· fonn ('\1' ''' 12 hr. O n days fi alll i 7. IIM'dldilll' , "II llral l~' ~·lT("l.1i\1" anti.lml)1hmic a~t"llt. is l''Omllllinislt"n "'l1 { 2ntl lll~ ('\1'''' IS hr \I arti n~ a t tilt' tim e of hlcJOlI \;llll pl i n~ 011 day 6 ). 11K-' oral ahsorpti llll of Iht'l'PI I~1 Iillt' is \i rt ually complet e (F = I ) ami G" IC is appnnimah,I,· I. IllSuffid t-nt information WOi-'i provided to conclude whether or not IlK"u lcti llt" aIn-red 11K" half-lift' ~If thl'liphyllilll'.
2. .
CHA,PTH 17
INTUACnNG DRUGS
1t n.-p1t.,tII_ e.-_......_
, ..... 17-5. M __ r
tIM M_I........ 112 hr ...... '00••, ..._1. .
"'''''
ItfA,T/VtNT
De_.·•.•
2
3
4
5
0'
7'
8
Q
10
00
7.0
07
7.0
02
117
125
80
55
Concentration
lmg/U o~ fooor,~. '"
0
PI. . . . h ...IetI ......
v",* J l floooo
0. """-'oed n. . 5O?Q9-Xll, 1001
'Mo...... «><>:J-,,-.d It> 3 cb. 1200 "'9 -v 8 lwl
a. Give an explanation for till' (·ff('(.1 of mcxtletme (Ill t1ll'u p hyllilw kinetics . The explunati on should
hc.' I"l-O;(,(! Oil a d mllJ.:(Oin only 0111' of till'
rol1 o\\i ll ~ pa mlllt"lt' rs : j ll . f ll T'
Cl"h" Q". Give.' til(' paramete r mvokr-d a nd im lilwdh" ti ll' din"(.'tiull of its dmll ~c. h. Brit·fly di sc uss Iht" explanation in (lut~ti nll "a" aiM)\"(' ill terms of 111\(' physioln¢ c.· mechanism (e.g .. (·1I7.)11W ind uction , com potuiou for ad i\'t' reabsorp tion in ren al tuh ull', lnluhit ion of biliary tou 'n -lion ) that couk] pr oduce- the interacnon. 5, Dr ug A is ¢\'('ll by infusio n ot a rute o f 2'5 mWllf to mainta in a con stant pkeuia concentrarion. The da ta in Tahk- 17--6 a n ' o hlailU'11 ill a sllhjt'l1 who is infuSl'11at t his rail' ill tlu- ah st'lIl't' alit! p n S('lll't' of D m~ B (il...~ U lI1 l· tha t it is it! sh·atl~· sta te when pn·st·"I). O
,.ltle 17-e. PI./Irt:AU PlASM'
CONCENTtATK:lN
'" reoo e
"""
DATAJO OOJGA
"""'" ""'""
CONCE N!R.A OON
0
20,0
"""
~1:«:if TK:lN
fRACTI()N ~
lATIA' STt.IDY Sl Art:~1
N ""'""
,
100
01 03
15
07
..,
HALF tJ!
12 8
G in ' u t his illfonlliltioll am] tilt' ob serva tlonthat tilt' ('f(' a tinillt' e!t·.mUl('(· inlhis SUhjl"(1 is 120 m llmiu . a. Dt.'h ' n nill(' if thr-re is t,\idt·!lt't· fo r DnI ~ A I It' i ll ~ st"(·N.'lt'1l a nd/ur n'a hsu rllt'1l in tilt' kid nt"')"S. b. Det ermine till' IIlt"(·I.a nism (s) by which DnI ~ B interact s wit ]; DnI ~ A. c. Discu ss the therapeutic implicat ions of l'o'l( l lIli n isft'ri n~ DnI~ A wi th D rug B. 6. Table 17- 7 contains pharmacokmctic \ 11I m 's fUf lU I im li\idu;u subjt'l1 l hlll t~]li fy what is known about til(' inteructiou between Ijuin idint ' a nd d i ~u'(i n ,
,.ltl. 17.7.
0 75 075
" 0 72
101 51
500 '40
077 079
~"" C... <J ~ ,. 1-3~
a. Brielly comment o n how q uin idilw alTl'(:ts til(' d istri hutio ll of d iv;o1iin. h. Using th e a pp ropriate d i ~o'(i n par,lIlll·tN \'alut's in Ta bl t' 17- 7, calculate tlu- probable "lo adtug" dose of digoxin nl,,('1lt'(l when tlwrapy with t his dm ~ is ini tiate-d in a palit'lll who is lImlt'rgoin g auttarrhyth mie tll('rapy with quuudiue-. TIlt' Iht'rape uti{' l1l1ll't'ntr.lHoll r.tll ~l'. 1 to 2 IJWl.. n-uuuns tilt' same for
'"
CHAPTH 17
umS ('tlllt'llt"t' of ad ministe ring quinidine 10 a pat it'1I1 \\'110 is rt't"t'i\illg di ~(Jxi n tln-rap~· . 111is is Iht· more rtmunon situation ill \\'hk-h Ihe interaction is observed. US(· tlu- t1i!-:(Jxill pa ranWlt"r values in Table Ii-i and consider tilt" events upon lxuh initialin J!; and d is(,olliintling quiutdine coad mt ntstratlon. d. Do ~ Ull thi nk lluiuidill(' would affect the dosage requirements for digoxin in a pat teut \\111. ~'n'n' renal [unet ion impaim lt"nt? Briefly di scuss. , . Bt' ~S lrull l 11 £II. slu dit'tl till' pharmacokmeuc interaction of the antidepressants 1I11oxdim' and dt ·sipraTllillt·. Fig-lin' l i -1 3 ami Tahlt, l i --8 sunuua n ....t> tilt' ollSt'rva tions folliMing a singlt· ural doSt, of desipramine (50 lIlj?;l alone am l3 h r aftt"r the eighth tWily dns(' o f IIl1o\t'tiTw (fiU 1lI~ t·at·h ). TIlt' ccucentrution of f111o.\t,tilw durillg tilt' tim e desipnunnu- is lillalltifi('t! remains rdatiw ly constant (half-lift· o f lluoxet inc = 3 to 4 days afler m ultiple doses). 111t" value of for deslpramtnc is about 0.0.1 .
Ie
100
1'-11/:. 17- 13 .
M,."',I't...."'..o:tllu
·".
l ration of (It-sipralllilH' ..fto-r ;l St l- m~
"ral d,,'\(· ¢"'fl aIe,,", (I>lade.) ","I ;1f_ t ..... Ii .L.ily .1t1'M (fin mlit ,-••eh) ,,( H"'no"i,"' (o:t ,lt'r) . ( ~ ,,"hn..,j fnlln Bt·l'K'frum. Itt'" 1'.')1u" .... .I ~ . aud 1..-", lw·'1l'·r. L : Q"••nlifX.at iun aile! nlt'( .....ni.m " f tI"" Ihll"""I,,,' and lri (')~1it·
an titlc-pn'\w, t
i"lt- r...1">I"
e ll". " h.an n..."". 11...1 . 51:2.19--2-11>. 1!J!J:2,)
o
2
4
6
Days 17"'~ Ph.......c.kl_tlcs.f D••lpra.l_ 'MM. AtiI.I.I.tareti O_11y I•• Iln,l. 50..., D._ AI••• and ....., II,ht Dally Da_. " " _ • •
T."'.
H_-
28.1 9 ,4 53 16 1 289 77 1
:!: :!: :!: :!: :t :!:
2.1.1 54 16 52
168
2110:l:Q()() 23,9:!: 56 68:l: 1 I 63 .8 :!: 19 3 27. 1 :l: 103
398
19 7 ... 77
a. ( ;i\"t'll that tlu- hltIl Il.Vpl'l'>ma coucent ratum ratiu of <J('sipTiltllitll' is close 10 l.O,l hat til(' dm ~ i... uu-taboli ....t't l llllly ill tlu- Her-r, and that tilt' "well-stirred" model of ht'jl
'"
CHAP1H 17
c. Brit,fly explain wll)' tIll" factor hy whit-Ii half-lift' is a ltt'rt,<1 is 1101 till' sa ult' as that of C I1 ,... d. \ \ l lal implicatious do tlu- nhst'lvatiollS nf tlwS(' authors han ' for til(' o uwur rvut adminixtrunou o f tlit'st" two
CHAPTER 17
~~ ~ 0
ggi ~ .~ ~~
e
~
00 !!
9B
~
<
g
~
u
~
0
-e
~
""1 0i ~
i1
~i
1:1 :;:1 ~
-b"" ~
o
~~l
11 H U -j 'lil'l'~ l 1 *L t t t i itt12 I"" ~~
0
5°
s
....
~ ....
1:0 ~i~! ill dili hlloi "" ~2 ,,1dh ,,1 ~ ~
• iJi
"8
.~
5
Vi
""
Vi
Vi
Vi
-
so
0
~
0 0
o
-0
o
o
~
~-
~-
0
ggi ~~~
r-,
0
~~ , R h ! 't ~
0
0
~
o
<3
0
~
0
-0
~
0
~
0
•
~
~
....,. -
u_
S\
0
8
~
1~] -
L
~
0
~
Ihu
0
~
-
o
1,
I I,
,l
J
CO NCE NTRAT IO N MONIT OR I NG
OBJECTIYES The leader will be able 10: 1 lis. the oeeoc lor detet"mining when monilOring01 plo~drug concenlroliOl'ls and applying large! coocennouco S!fOlegy ole oppropriOIe 2 Describe how popJIo1ion informolion con be osed 10 oblain inirial estmlOlM
of on
indivi-
dual's phofll'locobneliO
3 hrlmote the likely pOOfmocokonehc porcrreer values ,non individual patient, based on both popukJllon and porienl choroctefislics. for di9O"in. gentamicin, phenoborbirol, and rt-,e.
ophyll'ne 4 Calculate the pkwno drug concentrotionlsl expected or the lime(sl of sampling.
USing 8$1,·
malad pharmocol.inetic porometer vol~ and ~ing hiSlCWy of the P'Jlienl
5 Upon e'It'CI1U01ion of 0 phannocolinelic problem observed during chrook drug lhero~, ascribe the problem 10 a change in bi<:xNoilobil,ry, conolcrce. clearance. volume 01 detributIon, or a combinoliorl 01 these coloes 6 Revise pharmocokinelie poramelefS hom rrecsured plasma ccoceoecnce dolO acquired
under either
~Ie Of ~IotecoodiliOm.
7 Use the revised pClrOmeleiS!in objective 61locolculole any rroddcoucom ~ required 10 ensure rho.
the plasma ccocenncnco lies within the lherOpeutlC w,ndow.
DOl~' art' ,Itlm illi, lt-ft't l lo uchn-ve a th t'rapt'u tit' nhj ('t.1hl '. Onl" th i ~ o!Jjc'l1i\·I' is dl'fifl('ll, a dnl ~ illlt! ih dOSiI~C' ft~lllt'll an- d,u '>!'n fur ti ll" pat it'n t (C hap . 13 ), D m ~ Ilu-rupy is slIh'>!''l Ut'ntl y lIIilll;l~t 'l ! .lS Sl.O\\11 sd lt' nliltkllll)' in Fi ~, I ~ I h ~c,t ll('r with shops requt n-d tn inifiilh' tlll'mpy, Th is 1lI 'lIIa~C'lll('nl is lIS,mll)' ael,(lm plishe'l! by lIIelll i to rill ~ ind dt' ul" am i inlt'll sily of IMIIl. tll('rapc'lll ic and luxic d Tc'l'ls . EXillllplc's of this lIw lh od of illdi\idu al i 7jll~ IIlt'r ap y an- WWIl in Tahlt' IS- I. A1t llllU ~h pn-ferahl c, it is nut alwa)'s po ssihk' to II'>!' " d ill-"t.1 me-asure u f the des tn-d t'lTc'l1 ilS a tllt'rapt'utic c·mlpoilli. Snllwlin it's . si~lI s of to'dd t)' iln' usc''l l .ls a dosil l~ gurde . "nit' d nsc" of Siu il~talt"S, for example, when 1Isc''l1 in til(' trea nueut o f rhe lllllat i<.' (Iist"
1111' tllt'ra pe:uti{' ('lTt'('h o f Sillil, h h's, t1u'llp hyllim', ami arropiuc, ulthough uflt 'n sllhjl"t." tivt - allt l \'
CHAPTH 18
CONC ENIR,ATICN MQNlTOf/NG
29 .
Examine Patient, Collect Data, and Make Diagnosis
DefineTherapeutic Objective
Choose Drug and DosageRegimen
-.- - ---1
• Evaluate How Well Objective Has Been Achieved
~
Stop Therapy
"
ContinueTherapy
. '11:' 1"-1. C;'·Il<·r.J ...·11<"111<" f" r iuih;di" n ..ml n n..):t·nK·nl " f . lnll: IIK·r..!,:,,·. 11..• " ....jllr t ..., 1... ;mo ,Io·fini"!: tI..• tl,..rdl,,·uti<' ,,1oj<"1i\ ,",d ot."i".: 11K' .In'll: IlllO l ih 11, 10:<· n-¢lI l<'n. •1l"1.,,.,.]'....lin1/: I,,,.,, "..tl lll<" "t'j<'<.1iW I...., I......n "d ,i,,,...I. \ 1"" it"";"1/: n"'I....n,· i.h i" , ..,tll!'h. t.in1/: II..· L.., t 1\\.. l"-' It. . \ 1,. ,il"";"1: 1'La." ,,,, ,lnll: n"... ·nlr. tit'" III••· ..I.. , I..· II<"II,f,,1. ."I....iaI':-·if n I ' (11......"(""'1;,;, &1..1t.>1;,;,) ,.. ot ".·Il'I'l.lII'tifil..1. llot otlo1' 11,,· f...... II_ ·k , u, K...Jly .....I"i...........It·finil;,..' IIf th.· ' ... -r"1"·,,Ii<· "I>j<'<.1'U' • • ",·n
CHAPTI R IB
CQl\K:ENTiATION NC.lNlTOI/ING
therapeutn- success. Toxic eIT("(.'ls lhal ('iUl II(' rt,,(tlily meusu n -d, t' .~. , ataxia. han ' tln-n-fore h("('11 used to :L\sisl in d t'l t'nnill in~ 11ll' lIppN limit of an epilt'plk pati eu f s dosa~e requi n-nu-ut . :\ similar sltuauon urtscs ill till' uS(' of orul ilUtk oa).,YlJlallts ; the thc rapeuuc uhjt"l1ivl' is l ilt' pn-ve-nnon o f thmmlHH'ml HJlk' complications. A~ain , tilt" therapeutic ohjt"l1i\·t' cannot n 'mlil)'I)(' ll-\s(' SS('( 1. :lIltl then-fon- an alternative, simph-, und rap id labo ratory h'st, p rothrombin lillI(', wh id l II\t'il\ lIrt'SIhe h' nd t'lll'y of blood 10 d ot, is substu utr-d a." th e 111('r.tpt'lIti l' ohjt"l'lin" l J kewi se, for antihypt' n'hnlt'sle m lt'mk', h}"po~I}"I'(' lll ic, and uri cosuric i\~e llt s , d inie.ll lalHJralory tests an ' t' mployt"{l altematiw tl u-rapcotic eudpoiuts. Ck-arly. tn IH' IIst'ful, alte-rnative h 'sts mu st 1)(, ~r.1( 1("t1 amI d ll~t:ly related to Iht' true the r apeuti c e ffect. TI ll' seriousness of tilt' first !uxil'dTt'd o l)S(,,,,t"tl is a majo r dcn-mnnaut nf \\,I\('tll('( il ca n o r cauuot 1)(> usee] a." un e-ndpoint . TIl(' titrafkm o f ~uu n~ ad ults wi t ]; rlwlIlIl
exist in
a\S('Ssi n~
nystil~mus and
,t"
T.ltl. 18-1 . " ••pl•• ., M........... I•• T....
_It,........
Drv. TIt.,.", It, tIM lHech .....tI.cM oe.sE'iV"1lON oe.sE'iV"IO'l
SoUGGf SII\IG 1'£'f 1<SlO
CC«JlTON
5l.GG(SING~
at CfC lI'fASI'G
ccsoe
!'JOS,l.GI'
Group I Drugs !'Aonito,ed by Cbmcol Signs and
Sol""""
Rheumatoid
omlf;li~ 01
rheumatiC lever
InodeqUoliJ lEId...::tion
cJ jnf\ommofiOn
Sym plOm~
TrnrlllU~ .
"(MOO.
"O!Tl,I,"9
cod pain
Edema c cccced
E><eeUive eOOrno
w,rh ~~
CO,diOC foilvre. (.irthos.i~.
d.secse D.p".."""
Corbidopo/ Io.odopo
reoo!
Sh 1 l1'f IOXlC SIGNS
Fluid cod electrcf.;1e
.
s..-.
«ebcc-ce
hypoIen~ion,
cssocosed w,rn
eo-d-oc
,~
dSlu'borces
dehyd,ot>Qll InodeqUOI8 eIeYolion Dry mouth, blurred ...;~ , decrecsed 01 mood
Coece 1O_;C'ty,
!nodeqUOIlt conJrOI 01
InvoIu"lOry
d;~
efIecl,~ [),.4ine~~ .
bIepho'O$pO!>Il'l
--. -"""
OI!hoslohC
_~I
changes, ced
depre»ion RespllolOry fo,llI"e
Secee depreUian
01 'enol ,,"octiOn
Hype
f>rovmlo'""
~ymplOmOlt C
ekNollO/l 01
N\o, ~ed pe<~ i~ l
use '"
eoosomeoses and
trO"$Omioo loli!S ,
crecnoe
m,opo.~
~inole
Decrecsed se+'VIT1 ~'K:
oc:id
Go!>/TOOl'lleSl'rool ''',lOlIon
CHAPTEi! 16
,.,
~ l oTl i torill,g of t111'r,lpl'utk- respon.'>(·s and toxicity is best accomplished when mteg rated with kinl'ti l: l1llll'(')ltS. Iialf-lifl' de-te-ruuue-s the tune course of accumulation endhence the development of f('sp
TARGET CONCENTRATION STRAHGY T his slr.lh ·K" is usefu l ,t.. an atljlllll1 ill i n i ti ati n~ and 1I1 1111it {J ri ll~ dOl ~ therapy wln-n a numla-r of criteria hsted hdow an ' s atisfied . So me o f Ihe cri teria aft' absolute in nat u re, others an' rd atiH·. ~f ost of tlu-m. howl...v r, mu st II(' nu-t fur tilt' slmlegv 10 II(' R1ul irlt'ly 1'1T11.1in '. TI lt' ph .. ma coucentr attou of a d m~ must co rn-la te Cjllanlital i"l'Iy with hot h tilt' Intensity and pmhahilily o f t1lt'I'iIPI'1l1ic o r toxic t·ffl1.'Is. A direct re lation ship be tween cou ce nt ratk m and 1'1T11.'1 may II(' illSuffidt'n l grounds for plasma conccutranou mo nito ring if tilt' tlw ral'li'lltk l·ffl1.'1 ilS/.'lf is t" t~i ly monitored. whic h is fft'
. .4
CHAPlH 18
CONC f NTiA TlON MONTOfING
,.1.1. 18-2 Info Pllla,l.ft Pa rtlne ..' t. th o PI. a",o Co n ca ntra t lo n Monitoring .f
S.I.ct." Dru,. -<
C",c\o~p(r,~e
i.,·, •A'1<
'"
Autoimmune d~_
;>.A'''';.'~
". "
"'-,
.,
" " , ' 1--"
''''''..I',
E" eoS1Ye"
Phenoborbitol.
bccod
"fompin.
'Q
I 'DOP'c!f>J"'~
ood hboO
,
.' -.« 'Af>
.,.....
"
Sc-.e ,.,.,YIW ""J.'·W' . "
,.""
~ '.';"
',, ~
RenoIlO>:oclly i~ fJIOto' ceeeeo-
erytfwCll"-,<:1n, ,~
(~Ih
[),'l0"~
RenoId,~.
Di~,woon
D;.",relia
:r'"
,horoclet'lta
cc Ioilue,
rhyTooddl~
(;e.~ 'Q ""( I"
Some penlCiUiru
Renoldl~
Cenpesed 01 Ihree ;loOfl'IeI'~
N.:yt" p",<' ne
AIooho/c """""
d" ecee
E · '"",,~,v"fy
ooo-d !O
<Joel g lyc: OPI OI" '" E · l<...",.~I ...
Qy,rnd,l'le.
I\uo.<el,ne. oo_~
.. I
P,~n'{'U<"
Renal diseose. dvoniC hepatic deeese
-
TI>eop'l,lhne I'rleumonoo, chlOl'lo(
"""""""
~od '
ot>u"','1 ~JfJ le f,
~od~
o
bu ~l~
deecse,
Volplooc ccd
corh:Jrnozepine omefidine Eroxocin.
ery,tllomycill. phenoborbilOl
lOH;d'o ·.'~o'
. ,,,.,
~"
PoIymo
......"""""" SoMa"'" meeobol;)Ifl
A\OO.lobIe on
~"'
"""""
and ~forrm
~rb;klte,
hepohcci~,
,,"""""'Y odoma
"1... ",_ ••
..
,
."..
art' n-lanve in that, I ~' monrtortug tln- couceutrutkm, adj ustun-ut s in d()Sa~I' can lit' lIlad t' fc)r aln-red p harmacokine-tics . A M.'nsitin', accu rate. and specifk ;l"sa~' fur the lim!, must lx- a\"aibhle. III addi tion, to 1)(· IIst'ful. the results sho uld 1)('available befon- tilt" lJ('d Il\('mpt 'utic dt"('isiun is to hI.' made, T Ill" half-life is a IIst'fu l indl'Xof this "tu m -ar ound" tillJ(" ht'(-'auS(' il is tilt' ti nu- In une in which accumulation 0 11 multiple t!()si n~ and d isapl)('amm 't' 011 t1i st"on l i llui ll~ a d m ~ occu r.
THE TARGET CONCENTRATION TI ll' larxt't ('o ll('t'nlmlio ll initially chose-n is tlJ(" value or r.U1~I' u f values with 11)1' ~n'a lesl probabtbty of therapeutic success (T ahlt' 5-2, p . 59), kt't'pi ng in mind thai the pop ulatioll \"alut, (or m.ll~e) ma)' la- inapp ropri ate for all Individual. lI i ~h er ('Ullt'l' ntmtitlIlS 1Il
CHAPTER 18
29'
CONCENTRATION MClNfTOl!ING
Fn '(IIIt'm) ' of lI\on i lori l\~ is a function of the presumed change in till' factors that inllut-ncx- d m~ n's!'MlIl'i(·. For csampk-, ti l t' plasma conce ntration of phcnobar lntal in t'pilt'ptic pal it'nls, whose slate of health and dmJ!; Ih{'mpy remai ns stable. ma)' ueed to ht' 1I\0niton '(! nnly a few times a ~l.'a r: mort' fn'(IIIt'1l1 momt cnng may be Indica ted if the patient's health dderiorah's or if t1wmpy with ol llt'r drugs is altered. Daily or even ilion' Frequent mouilorinJ!; of pL~~JlIa tlu·ophyllilU' concentrations may he m.,.,lt.,! for op timal n'\(' of tlll'()ph)'llilll' in tln- treat ment of an asthmatic patn-nt in an intensive can- unit, especially if l'()n~l'sti\'t' cardiac failun-, pue-umoma. Iu-panc cirrhosis. am! sllloking an' all presen t . T hese conduious alter tlu-ophyllim- clea rance . which is likely to lx' quite variable andunprrdictabh- in this sit uation.
PERTINENT INFORMATION NIIOED St,\·t'fal kinds of mfonnunon. J!;in'lI ill Tahle 1S-3 an' IIt.,.,!t.,! to e\,lllIatt' il measun- dplasma t,(lIlt't·ntr'dtioll l·ffid t·lltly, A hislo!)' of d m g adm inlstratlon. wluch includes d ( )S('S and tunes of dnsill ~ is mauda to rv as an' lilt' limes of sampling. Spl,:ifil' patit'nl population pha rmacokinette Information for Illoniloring d igoxin, gt'ntanucin. plu-nobarbital. and t1lt1IphylliTlt' concentrations is g1" 'n ill Tahl e 18-1 . 11lt'S(.' four dmj.,ts art' u<;('1! throughou t Iht' renuumh-r of this chapter as esa mph-s of the application of tlu- pn uciph-s of plasma dn l~ conce-ntration monitorin g.
EVAlUATION PROCEDURE U sill~ lilt' dosill~ hislory and 11ll" tillll'(s) of sampling. jlltl~lIle n l is 1ll't.,It't1 0 11 whether tlnmeasured \,;lhw(s) is a glxxl eslilllat{' of tilt' maximum, aVt'r'dge. o r mintmumconcentr atiou ut sleady state 0 11 a fixed regtnn-n or of a uonsteady-state co ncen tranon ts) obtained t'illwr shortly aflN s ta rti ll~ dosing or follll'\in ~ an erratic schedule. lI a\i ng established the couditiulls alltl an appropriate kim'lit· mode-l, a geuerally recommen ded procedure to evaluate nllt· or mo re {'(m{,'n iratiulls is as follll'\"S: I . Estlmute rlu- likt'!y values (If tilt' plJannal'Okilwtk parameters (F. Cl ... V, and hence ' 111) in Iht' pal it'nl !liLst'1! on population pa mlllt'tc rs. taking into account Ihl' patient's age , Wt'i~h l. n-uul Iuuct iou. concu rren t diseases, dmg the rapy, dosage fon u. mut e of admtmstrution. and all)' other informatmn ab out tln- p;.ltielll known to affet:t tlU' kim-tics of tlU'
T.tt•• 1 a.3 . DehI C.llect1•• H.l.Wy 01 Drug Adm,niWOloOtl
Drug, dose. dc»oge form~.
fOllIeS
01 odm i n i ~otiorl . hmes 01 odminiMfOhOft. compiloflCe. inpot.eolor
ou'po'.eO'll Ic-e 01 Sampl,"9 Irebt,Ye 10 p'ev,ou~ Oo!ot')
Prt'$ef'l' cod Pre-ocos 101 ony) PIosmo Dr'-'3 Cooceolro!>Om 01 POI'ent We'9ht, oge , gende< . Cond"1Qf"l oo.ng Ireoled, smoking. e/hnic;,ty, concurrent d'~loe)lQ1W l~ialiy eo,dlO'o'OloCulOr, hepot'C. ol'ld 'enol d'~loe~1
(1,0'10(01 SIotu~
loooo!Qf'y Dctc ~enol furochO
CQrI(:urrM' [)lug Thefopy Inrerochn9 drug~ Assay inte!ference'
Act,.-e ~boIlte~ A=J'{ I\o'oethod l'eplOOueibil,ry. ~~"''''ty , cod ~;fic 'ry)
Uwol Pho'mocok,nctoc Po'ome~~ AUOClOled W,rt>, Type 01 Poherl! in ~lQIl 8>OOv'Oilobili ty. obsofpllOf1 'ote COfloonl, ...dume 01 di~ ibution , Uflbound lrochor1 in renol deororoce
pIo$fTlO, 10101 d earOflCe.
CHA,PTU 18
d rug . :\ maj or Intent lu-re is to idt'n tify tln- subpopulation In wilko!. tilt' j);ltit'nt ht>lllll~s (Cha p. 13). 2. Usi ll~ tilt' appmpriall' kine-tic 1ll()(ld and the !l
pnate.
,
o.
,8-4. PetI lcI
Pepv.atI_ PINt....c.kl...tlc P........" ef DI•••••, , .IMIIn...p")"III_-
P"'M\fIUS
10
10
0 95 hyd'OU$
OQ(Na50irj
o 9 anhyd,OU$
om ,~ ltrle
Oral bioo'lO,labMy
o 75lab1eb 0.9 e&i>:j,
Volume 01d ,)ir,b,,11On
Il/lgl Clearance (tlh,/lgl Halt·Me (hll
OQ51iquidfllledto~
,
-,
aminophylline [i.v , use)
<00
072 CI •
44"
10
0.55
05
00037
0 04 '
104
07
F,ocll()l'l e_" e/ed
10
87
03
013
unchallg!!d T heropev ~,
wmdaw
Img/ll !~J Q~"""'_
..
0.00080002 0,00100025
~~_ ,
pee,
;1
1~30
10-20
43-130
55-- 110
" 0<X)' < ~
l>d od !dooodb,o W! ! ....... JJ
so-..g
aodW J Ml<>
'"""",,, <~ -dooogor ....... - """'. . . ' vllfl.9l • l 8 • ~] l/l'w ~ "" <>:>A ~... _ ~ CO'dooc: ~ ~ ClII./ht\gl - 000.. • 00],,,, ... 01~"'Odooo"",<_ ......
a.. a. ..
v.,
·Awooo............. _ 01_' . < _ ~
..........,.. 004b,otoo loxbboolow"' ~b.....,."'9 ago, <1._
aod ~ '*'9>
~ ,~~
a •
1992
a..- • 0 048, ...... a.. .....
eo-- .... Iact>t,~""
~
_ _ l'o<w>
"",, < ~ .,-
-
""' ~ ,eo_ ....... "-
........
~
os
cr cs
"
"
" 00
cr os
"
. ', '1 • OQQ] v /O, V and 0 --.....:1I.000o ...,..,.. < and d ....-r » 0 I~/a". Vlw ~ 1.9 r" • • 8 J1"' . .0... J '" ..too lac"" ~ ... ""'*'-, 0...-; 1_ IXl - ' .... .... _ rJ 0 :JO- ~aod oo.'f/' o:>n< ~ "'" ~ "" "" 8 ........ doM
a....
"e t
CHAPl(. III
2'>'
DOSING SCENARIOS CIMph '" fi alil l '; t1 mla iu Ilw hacir- n '1alioll ~ t.ip ' ","t'111'1 1 for f'\;III1;llill!! cnll n 'nlr,tliUII' ohlaillt'1111Ilriul.( HIII,I.t11l ·rah' ;1IIt! 111lllllpl,·...lu\t' r' 1OIIWII\, TI••·\(' n ·];,tiOll, l,ips ;m' u...\ su p pl" IIll'lIh 'C l \\ i l l. f'1pl.lliom. w h id l ;m' lI'it'flll for fOllr ;ltlllil io n' II, fn "jlU'llll~ OC'C 'urrilll.( 'ol'C '!Mrio" TIW\(' an' ,,1"'11 HI'" or 1lI0 n,lIo\( " h lllis'it'1I: W""II ;I pallc'ut is ou a (u llr· llll lPs. a"'\;I~ n1..olll11 '11 ill wh idl I",' iU!c'IYal, arr- lIut ' '' 111,,1, for (·\.;lI11pll', !oj ' \1 . I I', \ 1. , ,'i " .\1 " !J 1' . \1. ( M II ~ 'C I II" n l r~ (';1111'11 a 9-1 ~'>-9 n'!."ollJwn l: wlwlllllt' dnl!! is rt'p" ;lh'1ll~ illfll\('11 U\ ( ' f .1 pC'ri,"! o f tillll ' .lppn l,tt·llilll! ih " .M-hf,·; .lInl wl u-n till' do'o('s \;I~ ,1Il1! tI..· in c: illh'l"als an' l'ITalic.. ElIlpl.,tsjs IlI'ro ' is lOll s"'JI :2 1l" ;tI' Mho ll I' roJl'C"t IIlrt' . 1);1r111 11 J.trl~ " II ,I.·lt-n llllllll!! II... "1'P ro 'pri.tll- lilll 'tic- 11 1,"11 ·1 f.,r ,·,hm.d ill!! C'C llK'C'lll ral ioil! , ) al lill"'.' I ' If ....l1I lp1illc: Fur '·;Ic·II flf tilt' \I'C 'IJ.lriO' , ,1"so rl'lIo ll is a \\llllll"ciin hi' 111111:1. ilion' u pit! lIl.11l . ·IIIn lHa· tio1l: i.c·.. Ilw illlr:.IW IlUIIS uv .} h"l m a ppmx unation "llJ11i,,,. :\It,orpti ull tl, "(·rt' ,ISt ·, lh K111.t11"11 : II ,I..HIM Ill' 1.ll'·1I jlltn . M,"(1MiIIl , ,, 1H"1l 1lt"('C .......t f)'. IIsilll! II..· I,ri IK' 1'11... pn'\ iOllsl~ 1.....\ ill e11.11" ; . l-:\lr,I\ .I\l 111.Ir l li ",'. l '"!l''' o.I...I'\\;St· 11<"''11. clu\i ll\!: ;111,1 , a mpl",!! III"'''' .In ' ," hSt" t"" II ' I~ II,ISt'1 1"" tl... ~ .f · h'H lr dCJll .
I"..
1'''
.\ !tl.01ll!I. II \\tlllliel St'1'1n tlI.,1 " 1I ~"' ''l.1 cit ·, \\t.nld I!:Tt·.II I~ u 'lIlpli"lt" ,I... ''',1111.111'''' "I' ,I 1'C 'IK'C·IlIr.tliu n. Ii i, 11..1 1I1,,{"l.·, lril\ -.c:•. F il!:Jln' 1'l---:2 , J.,n.\, .1 fh ' '1I.cl. "" . fi\c..[. illlfol'\~a1 mllhll"I·.(I,~· ' 1"""'11 ill wlnch CllI~' II. ~' is mi' St '11 T" .1t"{'Cm llt fo r II,,· wis",,, 1 c lt-~ · . CII'" Ill" ..ls tc. \llhl l';tt1 lI.c· UIIK'C'n tr;l t ic"11' \pt't:1c"t:l ill tI..· Ii",. · ,.1' s.illl pli"!!. jf cIIlh 1111 ' mi s"' '11 clt- ~· ";.1 111 '1'" L,'iH'Il. fm lll ll..tl 1'\ llI'I1I'11 if no dCN ' \\i ts lllisSt'11 nlis C'.Trl"(·!i·UII is 1l;ISt '1! 0" 11.., Imnd plc' u f .ttltl lli\ily n l ('f>nn'IIIr.lliflll\ fr om " ,It·ll II.",· .\ 1 ,I II t i",. ', . I" II1Is "\;Illlplc', ;t l"l.11l('C ·,, 1r.tlinll j, 1lH'a.SIlTl"t: I at Ii me- t I \\ i t hin ;I clt...ill1! illlt 'f\ OIl 11.., n IIlI"l. 'li t ra!iun " \ I""(1c'1 l " i l l. "" mis "' '11 cloSt, is 1I ... a.~""'11
F · S · Do~
V
(1
• '1
11... p,lr.III1"',' r S. ' all Iortu fac1o r, i\ a 1'CII ·llid.·111 c'C,rr' "('l in!! li,r IIIl' k,dioll,II l"lIllIl 'UI .. I' ,1m \!:. It, liSt' is 11 1111''1''\\;\1) if tI... d uSt· and ('lllc"{·u t r:.t!illlls an- ' ·\pn·\\,,1 in '1I0r.lr '1IIi" .
~ .=,
1.5
J·ist. I ~:z .
j\j>f~~~\
c 0
'~
C
10
B c
0 U
c
sa
0 0
0.5
c
,
~
E ~
il.
0 0
2
-
--- --- --4 Days
6
8
II ",
.\ """.,1,1."" I... "h~ II, ,h.' ~""
fI".t"~' I "~ " "..0' ''1 rUIM" "
,'.t.!".'., n ..· ,1.'\,..." ..( il",
'n,,~ ".
I .. "" 11 .. · ~h ',,,,, .~" ,,,,
~"" 'nll~
1\
"l""~~'nl III
Ih.· "".., ·"rr-"",,,, ,,' m"' ''ln~ I.."" rl..· ,,,,,,,,1 ,I,,,,, 11..· ....I t.,I."nn ·"'r~r ..M' "r ~'l\ r",,,· f,~~ ... m~ rl..· 1111,,,,1.10 · In ,I" 1IIIII' J ""n 11"'11 h.· ",11111,,10,11 .. rl,,· .MT.· ,.... Iw.'" " ,I..· , ~I, ,,· . ·~Iw .... 1 ""I. ''', m'~.. ,lc · 1" " 1,I... """' ·IIr.~I ..", '''I".,t,,,1 "r rl , II",.' h~1 ""Is rl..· ""~",,I ,~"" I"" 'n 1:'' '''' I,,~ · t, , .",.. .. ~. 11..· ,~", ·,..,,,l """,.""......., ,.., rl,,· ,t.., ..fr,·r rl..· 1111, 1 ,J,...... 'I!J 11(' I , ,, ' '' I"·nolll"",,,I, . '11..· poo,..,..." Q . . ~I '" tl..' "~,,, . ~" ·Il ",,, · ' ·'1"~1, ..1 mtl ... POO'""'! III II..· ,I'I,~J\ I" , "~n.l'lo ' c'..,,· In,,,,,, , I '1',1. -1 ..1 11 \ 1
N'
CONCENTRA.TIClN MONI1Oi1ING
TIl(" conce nt ration expected from
~i\;llg
CHAPTH IB
only a singl<.· do'i(' ill tilt' tune (If tlu- misS(,,<1 doS('
is
.::5.-;;;00= ,. se _. -"
F_Clmw.d doMI - -~ V
2
w!lt'n' 12 is the nnn- since the misst"(l dose . 111l' couceutrution (':1:1>1."(1('1) in the tlll' rape ul il' set n ng is then
cIf tw o
d OM'S
F-5 - 00,, [
II
V
-.-"
Et
- hi - •
~
.k'l
I
3
wr-n- nnssedtlu-u
--"
F - 5 - Oo.. [ e V 11 . - ") wln- n- t 3 is t he
l illw Si lll'l'
tlu- o t he r
d OM'
' f!
_ ~ .. '~
-
e
- i"
'~
I
was mis sed.
9+5-9 Regimen I n institu tio nal s('tt i n~ mall)' dru~ art' W\l.'1\ ill rt'WIl1l'IlS snnilar 10 till' 01lt" portrayed in
Fig. 18--3. Such regimens have a 24·hour repetitive or rt1-.1tllar cyck- ( 'W II though thl' dosing Inte rvals within tilt' tlay an' unequal. TlU' ('x!x-ckt) conceru rancn at allY tum- during tilt, day ca n 1)(· \; ('\\'1'« simp ly as the sum of till' stee dy-s nu c couceutrations rt.sult ing from each of tilt" four daily dos('s. \\11('11 gi\'('11 011('(' dail)', lil t" firs l dose of the day is e-xpecn-dto )i eld a concentr ation. e (/ , ). at stt-ud)' state. wn 'n by 4
t·ll(. 11h3 . TI..· pla.. nl1,~1Ii l'" <.lIlt,, ·nlr.lliulI , >lrlt-J ...., .. ".iVf'~'
..I . , .....1,..••1.. 1.. (2 ..•...It' r "1"""';"1(
20
pall" w ) ",ill. " "'9-1-S-9· Iyp t· of n,;; nl<'n in ;111 av·
n.,..
;or.. >ld d,i lel, In 1M. l"UJ"pit- til<' ('OI It , · ,,· ,r..!io" . 2.1 1I1WL, ..I tI linK.' of tI.., I1 lOwinl( lit",,· t9 :I Ml _ . ".,., Ii " ... ) " lel .... i,... ffrt1 i".. (11 1'"'''' tit.· "" 'K"_ - 7 1.) 20 mWl.l. An ;'K'""ll-''' ill II ""'. 10 " ·n..n... ,1,1 . Ie , ''''''W' ,"'I · ·.'..r. rna" ., ,,, ItnKity . 1""1 it. larl;.. dllrin lt I nin !il. !'K",,, aft..r tI.... t .. .... at 2 1:Oll (12 a'lt l 36 "rl. 11K' 01""" , , 1 1" "'KiJ t'OIK' 'llI''''lion of 6.3 m,vI . I e) i, " 'I'"'rim. 1" "'''1. 11M- p;ll~il; lW' o:a-'" hi,'"r.... ( I mWl, _ 5 .5 11 ~1 ).
"I'li~
15
10 5
O +--------~
o
11
36
48
CHAPTlIl 18
when- ' I is till' tune tlllling tll(' ILlY hdwl't'n ~i\i nJ: tilt' do'K' and 1>;1I11pli n~ tilt" h loud . ·nlt' t111l('('u lmtiull R~lIh i llg Inun h'i\i n~ onl,· tilt' !\('t.'t'lld doo;(' Oil a (bil, · n"¢lIwlI is
5
when- t 2 is till' tim l' bd " l 't'n tilt, ad millbtmlilm of 11.1' St't.,lIlti di N.' aud tilt' tinu- of 1,I(le MI sampling. and so on . Thus. rlu- concentration l'xpt't.11'tl (III sud l a n.·~1l\1·1l i ~
+
. -I:1'l
+
e -~ "J
+
6
{l -e-'1 wln-n- t is 2.J h r. rln- dosing illtN \u 1 ill ('.u: 1I of Ihl' HIlI'l' d.tily n "¢ml·us.
Intemittent Inf"siM Model TI lt' ;uuino~IYl'tlSidl·s. e.g.. gt·utamkin. an' IIfh '!1 .ulm inb ll' R'tl t·\l.·I)· 6 10 .s ho urs I,:,' a constan t-ra te in fusion of t'adl doSt· IM 'r :30 to (lil mill . This form o f admillist mtiull is Ilt'itlll'r a lIlult ip lt·-
Ro ' (l C-
- e -I:, ...,
CL I
(I -
1
.-'1 • ••
_jt _
II
III
'",,1 7
wlu-n - t is tilt' dosin~ inlt 'rva l: t '~f is thl' d umlioll of lilt' infus ion : n" = s . J)( N.·lt,~, : an d t is tilt" lilllt' ill tilt' I'l\t dosin g illlN"al hdw('t'n Iht· start of the- illfu_\iou OIml tlll' \\itlllimwal of tl1l' hlood s.unph-. Part I of 11ll' t"- pl
Dose aad lalerval UaeqtHd TIll' situation in which neither do\! ' lIor inte-r....alhave ,lll~' dl ~n.'t · of rt1!ulari t)" is [o'( llIl·nll,. ob\! 'n 't't l ill t1wmpt"lllit· mlluiforing. In this situatiou. Olll' ca n simply sllln lip dnl ~ th ai
CHAn H 18
300
n-mams from pn ...-i ous dust'S wi th th t" realization tha t {Iost·s ~\"t' 1l ilion ' thuu fuur p atient half·lin'!' a~o ( ':1Il 1)(· disft-';ilnl('(I, Si lll 't' so little d n l ~ n-mams in thl' hody from (' ad l of tln-m. 111t' pl.o ma concentr atiou expec t ed after three lin","'!>, fur example, is
c· when- D IN ' \. s.;ullpling:.
8
Dosl'~ , ami I)t )S('.1 f('p n's('111
tilt'
dust·s ta!.:..-n ill l i lll4. ~ ' •. ' 2' a nd ' 3 Itt'(o rt,
Confidence In Esfimates To n 's; ",,' ph a rn lal 'o killt't k pa mlllt'!t 'r valm-s pmpt·rly. 0I1t" 1II11st (,,(lIlsid N seve-ral pieces of
lnfonuanon. InfonnatiolJ ,lho ul com pliance. hioa\·ailahili t~· . lillll's(s) of sampling (act ual versus report ed l. assay rt'pn )(l ll dhi l i ~' and spt'(i fid ly. ami t1(l'i ill ~ history: an' of pamllKMlIl1 i llllx Ht ,l!I (,{', One II1mt also .....t·ig:h lilt' n ' b lin' l'Imfil!t' lIl,,{' (JIlt" has in tilt' pa r.llllt'l e r val ues t'Slilllakti From Hteratun- data, pn,\; ou s t'xp.' rit' Il(,(", a nd n lll('('ut mtio ll da ta . Hl"l .'1I.1I (C hap . 13 ) IIMt litt' ml nH" rl.ilroUl IC'h "r \-ahws an" thl l'\t" t"sli nmh'1l lu apply to the su hpupulalion to which Ihe panent ht'I (}II~s . ~ l i S
• ·l lt· I ~ . n ..· !'....." "" u .... . ·" I,...' ;,..' " f ):1,,,t..,,,iciu . pr''tlic1t't l ,lll n l1~ ;Ill '- h.." , ,I<.. h~ into-no"; ... >t..""f:, , 1..1<' .. ,.. I f" I1, ....;,,~ lh,' " , ..·..1<.. 1 ~",i" .....'.t..1l1 ,... 1" illfu' i" " "f lh,' .Im!/,. d .......
1".,.
l.v. I.." ,..,~. "'-' -pI f" , .... , 11...1"..
\\1lt'T111..• ;ul"ll h"... (i" f" ' i" ,, tlunah' ..,. ' ..,1i, .. . il:Jlifit,.ul ["'<1 "f '....f·l,f,· (1,U I" ' ..·...1. il11o-n,, ;II" III j"fll,i,," C>Ul n " lIlt in •• • ,... ..·,...1......TTl..- " n..... II..· IIr...., Infi.·... >n "" ..1.-/ ;. u....l t.. t '.. 11,\.1.." , "'p""1 r<1 ,'o l1l't"" " ..Ii"". "" t1 ,in tl... illt.-no-..l. n....... n tl" ,LoII, .. 1..." . 1' >11 11... "'1""-1...1 fur ,til' p..tio·lll in 1111' lhin l ..." · I,i.t"....', n ..·"'".. oI.....·" ..I .." ....·nl,...lio..... " .9 ..".1 tH "'loI'l ~ ~ n' ."I..·riml', ..... 1( e l ( I "'WI. • I , ~ II ~ I J.
j",........
,,,,,...,,,,..,., .-..1"...
,.;U'('
,h.·
t. t
-g, 6
.s c 0
~
"1l
4
c
0 U
C
:§ E
'"
2
c
~
'"E ~ ~
'" Q.
0 0
2
4
Hours
6
8
>01
O -tA"'TH 18 pLa.~ II\;1 concentra non oht"illt"ll dllri ll~ such all Infu ston is il funct ion n f tlou, d t·ar.lIKe-, a nd \t-J UIllt" of drstn buno n (e llllp. 6).
rille '
n f atl llli ll i~t r.l·
9 E\a1 uahnll of a pld..\IIla 1111KVlllrd.tion requi res klMMi n~ wht,t!wr t:k' ilrdIK't' or \'nlulIll' of tlistri bn hon i.~ tht, IIMln' \"ariahlt, iUK I app rt"l:iat ill~ Oil wllich of t1 K""l ' two parollllt'lt'n 11K' CUlK't'lIlrdlKlIl is I!MUt ' l!t -pt·l Kk-llt. 11K' latter lIIay IlIt" cllIu idt,rt"ll fmlll tlK' t"'t' llb llt'pit.1t"ll in "i ~. 1S-5 dllrill~ tilt" illfusiun of a dmg:in thn-e- ~"P'lr,dt· ~illlat ic ms. III Ca.-.t· .\, IIIt, ,'a1Ut'" of tilt" df"ar.lIK"t· allt l \lllu lIlt" P;lrdllit-lt' n art" Ih l"N" a nlic.ipalt"ll. Iht, aWroIi:t' ,.thw~. In 11K' ceb -r two sit ua tjons, lilt, half·lift, is th ree fiult'S grean-r than tilt· awrd1tI' val ue, in Ca.-.t' B d m' to il tllrt"t·fnk! rt'l lut:tion in t·!t·a.rdnn" an d in Ca.'1' C due- to a tll n 't'fukl ilM..Tt·a",· ill \UIUIUI' of tli~ rihtltion . \\l th lilt lt· d n l~ hol'i n~ ht't'll ehmtnau-d. an t'a.f1)· l'tnM.."t'nl r,lhu n i~ pn man l)' a flllK1ioil of i nfu~iun r...lt" aIMI \ll1 u llW of tlisl rihotion. ,\["('()nL n ~', there h lill lt· vt rt ue in lakin): a samp lt, I.'fon· tilt' lI-~l loI1llo11f-li ft· to es timate the tll~t' rt'flnin' IIIt'nls IK .... it'l l In ...'h K"'t , th<-rapt· u tic concentratjous. .\ sh",ul)'·st ale l'Ofll"t' n trdtiun tlt-pt' IJ(L.. Uilly 011 tl.· rdh' o f adrnin istr.d ion and tiM' \a1I1t" of clearance (C hap. 6 ), .\l"('tlRlin¢~' , sa mplill): at this ti ml ' pm\idol'S the most l"lmfKlt' lK"I' ill l"ltim.ating doo;;in~ raw rN lllin'II)1'uh.
~
300 -U ~
;;; > ;;; ~
~ ~
<;
C
200 B
11 ~
e, ~
'18
J ,e
A
100
~
0
C
'-' ~ E
e ~
0 0
4 6 TIme (in usual half-lives)
2
.
B
x
nit, I ~ ..·.~l. ;"lt .. n",~"" t ·r""" inr,u"~ ' rn"lut''-; Pl( lho· ''''lI''Mll r.ali"n "" "III' ".. ...:I r·bf.. ,10hlllt- In pootirnl •.,11, ... rr.". ~,.],,,,, ol ..hr<1 u .l"'.... of .b.tnl..,I. .... c "d ,,1. a thn-M;*I ,,"1<1l1 in cl-rar1l;'O' and ;on .... ~ ... ohm ( ,1<~nl..r. IQ. C..... B 1",..,....,.."'""11: 1.'f'A"", l ho.... p.....nh. ... 11"'.'1 p"'" h.nnKllI. h.. l•...onty. Is ~· I_ .Io-... ~. n • • Uf. "';1llt III f<.., .. I...:Jf·I.. 01. ,\ h",. " h . I1........MlclI~ in .. oft. ,,( ..... nhortiun. ( ~ C. ill hIO, drll'l1...1 ill ...... uuwl h..oIf·bfe. " on ." ........ ;01.101 .nf,-.rnYhl lhr final pt..r...." <. ...... IT " ." . . .+oinn!
J.....~;.I, lorho
......a
P"'"l""" 11ft'"
( HAYlU 18
302
Salllpl ill~ 1K'r.\l't'!1 lilt' t une of initialin,g tl.t' infusion .un l st('ady stall' oft t'll leads 10 im 'tludush l ' info rmat io n . At two usu al halr-li"'l" , tilt" u h">t' rvut lon of Ih t· conce-ntration e x1)('1.11'(1. Ct">t' A. dot-s lint nn-au tli,,! C/. a mi \ ' haw th t, ("j)('("h-tl va llu·s. TI ll') ' lll ay both di lTt' l" ami fu rtui to llsly Ki'"(>tlu- ('sl)('t1("(!I"lIllI,· ntr. ltinli. 111t' IIl\n· r-t1.,m -t·xl)t't1t'( II'lIIlI't·II-
muion Oil h \11 usual half-li\'t·s. Cil'it' C. (1JIlI.I I)(· thlt' 10 r-itln-r all
illl'rt'il",,'( 1 <'!t'anUlI"
or an
illl"n';l'i('(1 volunu-, ;LS sho wn. III contras t . till' ohservation at thi s tiuu- uf a ('UIlI't' n l ra lio ll ('flual til III' ahm'(' rhc {'\lx't1('{! st('atly-statl' \'alllt', C(<;(' B. is a d t'ar indtcation that <'!t'ar.lll<.'· is II'S\ than lIsua l. l utlt't'tl. tilt' !-:n'ah' r this di fTt'n'lw(', t11(' low er is til{' probable vnhn- of d ,'a ralll"t' ;Ill1ll llt" ~n'a tt' r til,' needto rt't IUl1' Ihl' rate of admi nisl rat ion to ;l\"'oid Inxidt~·. III till' n -,joll of 2 to 6 usual half-lin 's, a major 1'1l1lsitl,'ra tillll in illh"lln'tilllo": il si ll~I(' ,,!l""'l"\lIlion is wln-tlu-r t:I,'ar,uw(' or vnlume of di stribution is tlu- mo rt' \'a riahlt·" Fo r examplt" d l'aranl't' (in un its of I /l l r!k~) of IIlt'opl,ylliTlt' n lril'S (!\l'r an t"iglttfold I';tng' · or mon-, pa rtil11larly if alo":" and diSl·.t...., statt· an ' (,(llIsid,'n'(l. 11L(' r'lllgl' of \,aIUl's for 111(' vnlrnm- of d islrihlllion (lAg) is only about twofold. Tll m . t'slimatt'S IIf tilt' d t';.II';IIII'(' of 11lt'()ph~-lIin, ' eall lit, madt , frum nOl\Sleady. slah' \111m's oh tailll'ti \~i l h i n Illis firne- sp.m . Ahl lllllgh Ill,' p n 't.'t'tli ng ('(llll1'pIS n-ga n ling es timates of paI';Ul wt C'T'S wen- d,,,,'dllp,,(! for uduunist ration hy infusioll . IllI"y ~t' nt" rall~' a pply 10 all fo rms .uu! SI:h,'tltlies of dnl ~ adnnnislralion ill!t-mlt'(l to pmdlll'1.' a plan-au concentration.
Revision of Parameter Values DilTt'n 'n ('t's ill o"""'I"\('t 1;111(1t'\I )(,(1t'tl e uuvutrutions S ll~t'sl a 1Il1l11IIt'r of possihil ilit's. For t·\amplt·. ti lt' 1l;llit'nt''i kint'!i t'S liMy lit· di fft'n 'llt than t' \ I"I<'(1I't1. lit, or silt' may ha \l' 11t"(·u 1I01l111111plian l. Ihl ' Siun pling ttnu-s m.IYnul lIa\'(' been no!t'tl t,( lrn 1.1 Iy, or au a.SSilY problem ma v han ' occurred. major t1''('isillll is how much 10 n 'ly Oil tilt' llIt·.l-s uTt't1 couceut ranon rl'llitin ' to informatjon knowu aho ul patn-nt s Sill'l l as 111(, Ullt · hl 'in~ In,.II,'(I. sudl dl'(1Sioll'i aR' IIt~,(JIl d tilt' S('( l!)(' of Ihi s chapter hili an' H' T)· important in (1111('t'lltm!ioll lIIouiloring. Fur tilt' pll'l)()S(' (If Illis ('ha pl N , III(' (,(lllt't'ntmtioIlS. dosill~ histo rit,S, 'i
11'1'
(ASI HISTORIIS Til dt'llllll\sl mlt· 111I' prill d plt's uf p!
0 .04 x 11 .6 x 0 .4 x 1.5) x 65 = 2.5 V hr
303
\\ llO' n ' CUI·l IAlrikt:: is t l... t ~ pi\ 'a l \"alll" fflr tllt""p l l~ll iH" ill tIll' 1II " l' m ,,~ illt:: l';tli'·"1 pUpil' Iatiull . :\n ( ~ l m "t 1 i o ll for 11ll' ;I1!1' of Ihh adillt i, illt,!Ilt !I"l,1. O lll' p\!)I'('h ;1 c1.·erl'a\(' i ll rh-ar;iII n' "ill. .11.:" . t -"Ill ·(:i.,I1~ ill t I... ..Ill,-rl,' 11.11it "Il l. II f 1\\ t '\ «r,
( 'I] rn "Il l 11 ... 1111 It).. fflr ,-,II 111.<1ill l.: pa ra lllt'!,' r \. ,111", Il.r tlU'UJl' I~I1iIl" tlo 1101 iudutlt' SlI('1. all ad jml/llt·1I1. It is import .1lI110 nu l!' IIMI mil " dl '\( '!opl'Cllwrt' MI' inlt'mlt"tllu Ill' (·\.;lIupl. ', am i 1101 In " II II II M ri/~ ' ;til tllal is ('lI rrc ,"t l~ 1.110,,"11 abolll II... l lnlt::\ ;tlltl tilt' \t r; lte ~i .... ' · "l plf~. "t1 lIlT 11." 11I. Ct · rt ailll~ . ;I' mun- i" ("TuMlinll is u btlilU "t l. m-w am i nnm- n ·fillt"t! n ·lalioll , IIi!)\ \\i ll t tt, fnrtlu"t 'llliut.!.. C;I\(' I.l)iK,lJx;ll. \ 1..... 1).11.• :1 .'i: I '~ '·:l r-ol d . S:!-lJ.:, Il:tt i.·nl wi llI ("I J11lo~p ..lh l· ('llrd ial' fllilun- fllr 11ll' p;I..1 :1 ~ (· a ...., n .I" lu llllilh ·d nn .\ I)ri l Hi III I llI' 1"1'>pilal III H):IMI bc cau...• Ilf 1I \\ 1I .....· n i ll ~ u f her .'1 ln ~.·..li \.· card iac fl,ilur. ·,,) IIIplom... 11.·r m lm i"iu n hi ..h,l')' indi.·.l lt-d Ihal ..Ill' h;ad Il,1.1·1I 11.' r di,t.:,u\in I"bld lO.:!:i m .Lt) Ih,,1 II mnlill~ III t he u"u:II lillI(- ( ~ :( M )-H :( M )) _ h UI h:ul f:til.·(lto tllLt· a tablet 1111 IIIl' IU('\ inn.. (1.1) (:\I)ri l I:i l. .\ I,la..nm ..lu n lll. · IhlIIOI(1 n il hl lran n ;11 I 7:IMJj n .... u h l.lillt'd til "'-e if IIII' ..) m) )hlln.. ".'n' ."II11..i..lt-nl wi t h nUII.'1 ll1lp li;u WI-. :\ 1));1.. 11I:1 di J:.u\in ('1 I11("l' n l n lli n ll u f fl .!'
~ Wl. illlt! .. "" nllll ('n'nlinilll' uf IUJ IlIWdl. " l ' n ' n 'pu r11·d
\'",,11'"
SI, , ) I. f:.. /j"",I;,III ,1f:r/ " ·d .·,II'll m"'d ' ·" F rn m a~' · . ~" II, I, · r. cn-atiuiu.-. Ih.· (·rc-. ,Iillilll' d .·.u .lIIl'1· lTa lll.· If')--2. I). 1>' ) i..
\\.+..:1.1. ;11..1...-n nu
, (1 40 - 5 3) )( 8 2 - 93 ml/min CLc, !ml/m.n) 85 )( 0 .9 15.6 L/hr or
0 .068 l/hrt1:gl
Cl ll/hr/ kg)
=
0 .9 )( 0 .06 8 + 0 .02
IO.0812l/h,{kg Of
\Ill/kgl
u
6.66 l/ hr)
3 8 + 52 )( 0 .068 (7.3.:1 l/kg
Of
60 2 II
E lim ilial illll rail ' l'I lII\l. tlll ;Lll.I It"lf·li f., arc- 1110'11
k . CL/V = 0.Q11 hr-
1
'11,,· \ " 1,,.·.. "f.li a u,1 "' I" r lIn · lI l ra l ioll . I'rt·"lImahly. till' IMlil' 1l1 I" 1"'1 '11 t;\k ill ~ t1i l,:f1\ ill fur 3 )',.;u"'. 11... dll..ill ~ hi.. t ll~' i1 11!i('ah' .. a \i ll ~ll' , n -....·lItl.\ - mi ~1 d -. 1'1...... ;\ \ It'ady -\Ia lt· 1111 111,·1 ill( ~'I'] )Or'll ill l.( IIII' lIIi.......1 d' N ' h app rup ria lt·. Ik f..all · IIII' ('\1)("11,..1 hal f·li f,· i.. fi.1 hr " lid II". l im illl.( illl"r"al i' ::!., hr. Ihl' 1l1l('lualioll ill 1~ 'lIn 'III r;ll iflll ..111 ",1.1 1)(· minor alit! ;, ('tl1l..l.ml ·ra!t· illf" ..io u mod ,·1 ..I.. '111,1 a ppl~ . ,\ Ilc-m ,.l h ,·ly. •1 \1t';uly· "l.Ih-, lImll ipl.·.d' N · IIMIIII'I .... 11I111 111' . 'lIlpl,~ , ·. l U \ i ll ~ th.· ulIl.. I;IIII,r;clc- illfll ..iull mul..!. till' ( 'tI II .... 'lIt r;.tio ll "·\I )('l1 ,~ 1. C lf ) ( Fil.(. I ' -::!l. h 111l' 1I C•• - C (/ , ). \d n · O t l ) i.. II... (~IIIl~ ' I I Ir;ll i(l1l "O\p' 'l1''1132 hr ..rltor adlllil1i..l r;'l io ll l ",d lllll~ Ih, · mi....... 1 Ii · 1" " '11 ~i\. ·I1 _
CHAP1U 18
CCNC ENTl "'11ON M()NITQii:1NG
304
F ·5 ·Do~
CL .
t
C.
F ·S·Dout ·e -I.'l V
Cltll
Usi u!-t il skady·<,lah', lll illti p lt' "",lc)'i(' II\(Mlt.J, tilt' couce-ntrution j'xl'lt"(11'(1 is tha t S hr (t ~ ) inln tilt' 2-1-hunr dm i ll ~ inte-rval (tl minus CU. ). ;lS dt,fill('(! aho\'l' (II ::: 32 hr).
111t" values an - O,ll') und lcl l lllWI.. it tlilTe n 'l\('l;' t·.\pl aillt '( II I~·I IIl · assum ption of l/l:auf!t' ..It'itt!v-slah· concvnrratiou iu tlu- first IlllM lt'!. St~·p 3 . CO"'Pflri~OU of oh.' I'n-nl (/lui f,XPf.·(1f·t/ Conccutranans. 111t' (lhst' '''I'(1 (0.9 ~ WJ .J autl l'\ !x"(1t"i1( 1.0 1 ~ WL) values an' \irtllally tilt, ~1II l(' . Sh'p 4. n ...i sioll of pa rallld N
values. is llllllt't't'!iSary . Furthcrtnon-, tilt' cluuciaunow IMs sm lll ' (."I111fidt·Il("l' l hOl t t ht' Il
=
CL ,. O.OA x 1.6 x 1.3 x 22 = 1.83 Vhr ~ olt,
that till' d l'Milll('C' pc'r
~llU Il~t' r
ki l ll,,~r.lIn
ill till'
fi-~l 'a r-oltlll( ~'
is ildjmft"t l by ,. f"(1m of 1.6;
cluldn-n (1 10 " Jl'un; of a~t·) art' adjllsh't l b~' a fador of 2.-1 (Tabh- IS--I ). 11K'S('
numbers an ' d ll'( ' In lIlt' values t'.\I)("'(1t'tl for atljll..lult'lIl ll. Skp 2 . EdillUltitlU (If f~If"t1l't1 Couccntmnon at 111111' of SfIJIIll/i'I/!.. U..i ll~ E'I . 6 . tlnUI Il<'(' IIIr.t1iu lI al "):on is
" vimilar situation is dt'pk1t'tl ill Fi~. l ~ . Slt'p 3 . C"'"/J(/n'ifJII oj Ob.~t'n"c'(/ mul F,J.'/1f't11'l1 G'l/In 'lItmtim•.s. Tltt' obwrved coue enImtilJll (6.3 UlWI.) is tlm "(' tunes !!n'lllN than Ihat (" I)('t1t'tl (2.1 mWI .) 0 11 rlu- assum ption Ihat lilt' illflln natillll un com phance. dO'>ilJ~ sclu-duh-, Silmplin!! history , ,U1d ,lsSily is ,11'(' 1mh' .
Slpp" . 1l" I · i.~iflll oj Parunwter \ 'fl/I/l'.~ . Appa n 'lllly, t'ithN volunu- o r dt'Mlllll't', or lxx h, Ilt't'tls n -vision. Tln- flllt'stiollS an': \\1.it-h IlIw ? a ml llllw mild. ..hnultl it II(' n-si.St."tI? On('
OWTE~
30'
18
,lppru,l('h Wtlllld lit, to ;J.'iSUIlll' that Ihl' volunu- term is corre ct and cha nge th t' value o f k (o r CI.. Silll'(' k CIJ\ ') iu th e equation ahovt' un til till' r ight side o f the equation is equal tu 6.3. TI I1' flllln..~ill ~ vahu-s an- dcn-runned:
=
01 66
21
43
012
02
010 008
91
Thi s proccdun-, 1·" lIt",1 itrrntnm, is IIM't1 fn '(lut' ntly in di llil'al pharmat't,killl,tit-s. Xott' that till' mo st lik('ly ".thw of k, tu exp lain all ohservation of 6.3 lIIW1.. is about 0.10 hr " I . a vaIm· no t tuo t1ilTl'n 'nt fmlll tha t t-\llt 't·II'l1. U.!'i' !lr - I . A similar 'lilalysis ('{mid Ill' l'm ril'll n ut a.ssllming: that tlu- value o f clearance is th ai I'XI)('l1t'll ami tilt' ohst'l"\-atiulI is a n-sult of an nuexpected \ulu nl(' o f distn bution. In this
caw. tJ-18J >t 20IV
11 -
+
tJ - l U >t 16 I V
6 -1.83 >t 2..
+
/"1
By in-rat ion. tln- fonll..~i n~ vahn-s are t1d t'n nim'll: VIU 11
21
20
40 5.7 04
40 00
Xnh' that a la 'll:I' ineTt',N' in \ ' is 1lt '<.'(· S'i.;II)· to account for the observed co ncentration. Populat ion da ta on tl ll'llph yllillt' st.ow th ai ck-arance is much more variable (large r coe ff i('i1'1I1u f "'I riatiu n l tha n volunn-of distnhution. ACl:o rtlin gly. th e prudent decision is to adjust d l'ar.IIlI'l· and nol \UIUIlII' of di strihutiou ill thi s p;ltil' nt. 1111' pr ocr - dun- wlll'n ·hy till' .....nsili..i t~· of the oh M.·r\"l'l1 measure ment to ch an~l's in paramete-r \, tlllt's is ;1-~ st" SI; 'l 1 is <'11I1t ..: l .~ f'll-~ it i r lty tJ1wly,'fI.'f. It is accomplished h)' sp tt"llIati. m lly suhs litlllinl!: various values for each par,III1l'ter, ill tum. int o till' appropn ate kim-tic IIlIllll'l. Ti ll' l'()lll'l 'nlr.llioTl i, iUSI;'l1siti\"(' to a parameter when large d lalil!:l'S in Ihf' parameter prodno- small ( h U1I!:I 'S in ('tm('('ntmtillll and the ('()n\"('rse. \\'", ('(md udl' from suc h an ;\u;lly>;is. anti fmm our 1!:1'1II'm l kunw ll'lll!:{' uf th e popu l;ltinll phann ucokiru-tics of theophyllilll" thai dea r.tIll,(' (k • \') in this pat iell t is alx)1I1 1.1 Lzhr. The couceut ratu m is S('llsithl.' to d l'Mmlu', ,I.'> onl y a small dl b -st es tilllah' of the maximum l'tml'l' l1tr.ltit;n is II1WI.. 1111' roncentrution mll~{' ht,tW('t'1l a In lllF;h of 6 .3 mwL am i a pt·ak o f 2 1.0 IlIWI. n-uders concentrations outside till' recomnn-nded tlu-rapcut ic .... tndow . A Tl-gill1ell of 6- lu m rl~' fh''ll dust'S lIIar not 1)(' practual he n-. A mort' Inw ml st,luliulI is 10 s\\i ld l 10 a ('()Iltrn lll'll· n ·le;l
21
CHAPTU 18
Ca.... 3 . l..-nlt, miC'ill. \l r . H.G ., a 2.1-)','ar -o ld , 51S LoR patie llt "itll a Rra m -lle gati, 'e p nl' u n" m ia , "'a<; lx'inR treated ",ith Kenhunidn and ampicillin. Gen ta micin had been WH'n a ll Lv, infu"lion ( ~O mg) UH'r 45 m in e\"l'r)" ~ hr. Blood !'Hmp le !li "'l'rt" ofJlah'l"'l1 j u..1 lx'fort" lind 30 mi n a Oc r th e end o f Ih l' fourth infu",ion 10 prt"" e lll hnicilJ' a n d In evaluate h i", Ihl' rapJ', The Rl'n lamicin ('onl"nlralio n l; re port ed "'l'n.' 0... an d .j.9 ml¢ L The seru m cT('alin hw in lh l' patil'nt "'a '" 1,2 mwelL, Ste p I. f:..';lIlIlli",. of Paramet er " allll,s , 1111' ('rt'alillillt· d t'arall('t' in thi s patit'nl, e-sriliMit'll Ir oin tIlt' patk-nt's a~l', \\l.-i~ht. ~l' m lt ' r , and Sl.'nllll en-atiuim- (T able 16-2), is 79 1II1Jmin (4.• l A ir ). TI ll' dt';mUll,(' of ~t 'lI t a lllidll is appm, inmh'(l 1Iy r-n-at iuine clearance (Table- l b.- H. TIlt' \Ulunl(' of d btrihutinn i.. 12.1; L (0.22 IA R X ,').~ kg). 11 lt' t,!illlinatinll ral t' l"fllll;tallt a mi half-lift' an- tlu-n (J.3' IIr - 1 illlcl l. 9 IIr. rtOSpt'l1i\'dy. Sh'P 2. f: \'fj/lltJIiOFl of Er pf'("t'(/ Gllln 'IIlrntilJll' at Ti"U'., of SlI lII/ l/ili/!, . 111t' Sitm pltOS are ubtahu-dunder slt'ady.stall' l1l11d itiollS h-' lll'l1t'll half-lift, = U) hr ), anti tilt' dm~ ls con-
"!Ii
sta ntly infll'i('ll tAl'r a )"It'riod of lilllt'. .t.'i min (f).' S hr ), appmat"lI i ll~ tilt" ha lf·lift' , 111t' lntcnutttent in fus ion 11I11(11'1 ( El l' • . F :: J) is appmpriate 111t' concentrat ion just before till' TIt"" inful;ioll j<; ('1ll1ivul('lit to tln- \OIIUt" at tht· end of tilt· dosill ~ fnte rcu l (st't' Fi~. 1&-1 ). Thus. tilt' reuux-ntrations 3(J min aftN tilt' end of tilt' infusion (1.2.'i IIr aftN start i n~ til(' infllsill!l) anti at till' (·1It1 u f tln- IS-IIr iute-rvalcan II(' calcula ted fnun
C ..
- 0.37 )( 0 751
80 11 - e 4 .7 x 0.75 (1 _ e - 0
37 >< 9,
. e - 0 371,- 0.7051
111t' t'Xlx'(il'l ll1ml'l'ntmtitllls art ' " .S ami 0,4 mWI., n' spt'l1i n ,ly ( ri~. I ~ I. Stt'p 3. C"mlHJri~m. of 0/,-~( ·,.'t:4 'd ami t:X/II'(1I'(! COIl n'IIlml/O/IS. Sill('(' tilt' nbst"rvt 'l! a nd ('xllt'l1 ('l1 values a n ' \i rtually tilt' satm-, tln- est nnatr-d pa rault'lt',. values a rt' i\.s"'Ulllt'l l to apply ttl tllis I'alit'nf,
<:aq' .j.
PllrtwlHlrlJila l. \ In, J.p., an H2-J·t·a r-o lll, 5.'>-10." paUl' n t wtth K M' i7.urt" d iserder, has bceu n."('('hing 100 lOR o r plll'nobarbila l at lx-dtiml' Ior J·t'an . Sh l' IUmt'ician Increa sed h..-r n iglltlJ' dose 10 200 mR b ta rt l'
qtl! .
F · S ·Dose
Cl . t
lOOmg ..
0.2 V hr ' 24 hr .. 21 mg/l
A sh 'illly-sta!t ' l"flllstallt-ra tl' illfu.sinn I1Itl( lt'ln m~' lit, 1ISl.'1I II('t.l.IIst, of tht' short dnsill~ in h' f'\~tl (I day) rdatin' to the half-Iif(' (4 days ) OIlltl llt'l ' lUst' tht ' hlll(l(l is ~tlll p it'l l ll('ar tilt" mid point uf t ht' dosing illlt'l'\'a l. 111t' '\("t,lIld ]t...·t'! (~J Il II(' ('lleulalt'(l fm m a hol lIS plll.s l"flllsta llt· m!t' infll ",ioll IIItltlt.J,
C HAPT E ~
307
J8
1 day 200 mg/doy x 24 hr 0.2 V h, (I '" 36 mg/ l Step .1. Cm/I/Hl n .wlII of Ohwn:('ll (I/UI F.x} H'Cktl Concentrations. Clt'arly, tlw p,atil'lIfs oh"I'I"\ ·( '(1\ alut,s an' well lx-low tilt' p n -dicn-d oucs. Hevision of Illln lllwtt'r values is ill order . Sh'p 4. Hl'l' h io ll oj Parameter \ 't/l l/('.f . As neit her ccuc'e nt ratiou is a steady-state vahte, nOll-.slead y-"talt· lIll'tl.IKI" must 11(' U\("(1. Two appnJlrodw" nught 1)(" constdered . First. tilt" lllCKll'1alKln ' lIl i ~l. t 1)(· 1l<;(,( 1. I f tilt' vuhn- on ' h.t~ nTlly m inn r ' ;'lria hilif)' wi thin Ill(' adult population. It'' is IIJ(' case for plu-nob arbital, tln-n the vahn- of d l'ilr'll!("(' can lx- calculated by iteration as in C l
de
F - S 'Dose _ CL .C
,
V · di =
III t, mdit iollS in which the couceutranou d Ja n~es from one value. C (l I )' 10 another C (12), rl e Mt can
lit, apprll';illl
l'(I" .ltioTl 1111'11
q'd) := '11 On
C(t. ))/( '~ -
I . ) ami G I,:,' (C(, . )
+ C(' 2»12. 11lt"
!)( '('(mi I'S
F · S · Dose +
CL. 1q lJl
+
2
t
n 'a rran ~t ·n l(' n l .
F· 5 . 00•• _ V · Ig',1- g 'llI CL =-
t
ICI'11
+
1'2 'I! C(r,1I
2 Suhstitut ion uf III(' vnim-s fur t'al'" ~Ylll bul n il tilt" right sit!t· of Ilw t'(l" alioll ~n's
200
Ct .
24 -
30
X
(26 - 12)
(240 - 01 (12 + 26)
.. 0.35 Vhr
2 a '~I I ..(, r-krwtotlu- ('~li m alt' fm lll rho rirst mr-thod. In hoth cases, all t·slimatt· o f \ ' 11;111 In 1)(' IIst'(l. TIll" st"(' IJI( l lIwll.IKI is all «pp r odmutlon. with (ul1sidl' l"dblt> errur whe n e (f ] ) a nd (.'(I ~ ) an' d ust' til ('a d l orln-r ( (C ( f ~ ) - CU, ))1(1a - t I ) ca u then 1m.....' a high error] ur wlu-n e (f 1) ami Cl t 2 ) an' far apa rt [(C(, . ) + C(t ~ ) /2 is Ilu-u nol a ~I K )( 1 t"Slimak of l!J(' a'·('r.l~t· \'a lut, o f C dll rill~ tilt' Interval ]. III !-:t'lIl'raJ. tilt> U('ra li\l-' lIlt'tht KI is pre fem-d
CHA.PTE ~
30.
18
Otllt'T appnl;\t·!lI·San' 1I0W availabh- tneuupu ter pn'h'T".ulIs th at tucorponue population mean and \~lriahi l ily iuformunou ill ti ll' pa r.lIlldt·r values ami tlu- charact eri stics o f ti,e kinenc 1ll11l,!t'! ll-S \\l 'lI itS tllC' thud s) of salll pli ll~ and dosi ll~ history . Step 5. Ik o mlllwmliltiorl f or Mljusl" wI/t II! lJO-\fl1!.('. If ti lt, , bny , Ill\(' of 200 Ill~ is {1111-
nnned, a sh'atly-sta h'I't llll'('n ITitlillll of 2k IllWI. is t'X!'ll,'(11'(1(F · S . [) ' W'! t . Cl •. Cl . "" 0.3 lA,r). :\ d;li l~' duS!.' o[ 11M) 1l1 ~ tlu-u ~ \'l'S a (:u rn'spol1t l i ll~ vu hn- of 1-1 mWJ .. Bolh " a1I1!'S an ' within tlu- therapeutic window. II S('(' TI\S ap p ropri ate In conchnk- th ai th e patient has a Il i~l lt'r (50 %) dt'a nllll't' than ('Xpt'(:h '( t itlid th 'll silt' hat! ht't'u compltant be-Fore admission to till' nu r.;ill~ horne. :\ t1t'l;sioll IInw is Ilt't't lt't l o n li lt" pmpe.'r d INlV;e.', Bt't.'llll ~' silt' had 11 wtz un- O il IUO mWtL1Y, a daily tlllS(' be-twr-eu 1511 a lltI2(J( ) m v; see-ms appropriate. :\rv;u;,h ly, ill ;111 four o f lilt' Iln'C'('t lin v; exaurph-s, d nSlIV;I' ('(mid have ht"('n ;jtlj llslt'tl so ld y hy t ilralinv; to li lt' d Tt'C'ts observed. :\ poinl in fll\ u r o f ('(lIl(l ' n lm lio n measun-meut is t ha i an ;I.\StosSIllI'u l could be.' mlKle.' ;1.\ to w hy tm:it:ity or a b <.o k o f I"lTe.'(1 occur red. T!le."St' mea sun -ments ;jlsu pe -rmitt ed fadll" lind rapid es ttmatiun (If tln- pal it'nt' s dOSlIV;t' n 't lu irc. ' lIlt' n l , whid l o the.' I'\\iS(' mi v;hl han ' required a (,(lIlsid t' mh lt, d t1!:r('t ' o f readjustment from o hS('ninv; t!le.' e fTt't.1 s alone. 111t' fillt'm'ss o f tilt' ;lIljllsl lll(' lIt \ \1l-\ a! SC I 11111( '11 v;n 'a tN wnh tln- plasma concent rat ion data than it \\lluld han ' ht '('11 \\; tho u l tlu-m .
STUDY PRDBUMS (Answers to Study Pro ble ms are in Appendix II .) I . Lisl and hrit'tly -\.;V;. H -Yl'a r-nld f('m alt' patil'nl is r('t."t'i\ i nv; 120-1IlV; dust's of V;t' lIla m idn in sho rtn-rrn. constau t-rat e infusions ("'l' r 4.'> lIlilll'\l' ry " h r. TI ll' patlent has a serum ('r('ali ninc of 1.2 IllWd L. Plusuia s amples wl'n' ohlaiJu't l jm t ht 'fort, an d 4,') m in afh-r tln- eud of tilt' fou rth d ust ,. a . E sl im ate ti lt' \'alm 's o f clearunce, volunu- o f t!isiribillion. ami half-lift' l·l pt't.1t't l ill Ihi s palit'nt. h. E sli lllalt ' til(' ~t 'll t a lltid n ("t Ill("t;' n ITil!inll ill p l,I-' 1l1<1 t'XI:N"t1t"t! " I t,,,t'l i o f tlu- IW1I samplin~ uuu-s. 3 . The plasma ("t mn' lIl m tio ll\ a t t ht , tunes n f 'i;lIl1 pl i ll~ in tilt' p;ll it'lIl in problem 2: \\ l 'f\ ' 2.5 ami , .2 IIlWI.. rt'sl:N't1 in,ly. u. Usin g Iln-se I"tJll('(' ntmt iu lls, n-,1St· lilt' tost im a tt"'S o f d t';ITiUlt1.' , vohmn- o f dist ribution, a m i h al f-lift' in this pa tient. h . Is il pos sihlt' to adj ust lht' doS(' (t Slllllt') to kt't,p l ilt' t n ltlv;h <~ ltl("t ' II I Tillinn 1:N' lnW 2: 1Il ~I. a nti t ilt' I:N'a k ill:Nl1."(' I) Ill~ L? 4. ( :i\'('11 Ihl' IIsu,,1 para nlt'ft'r values fur theophvlltm- (T ab lt' 1~ I, p rovtdea pharma("tl\.;il wti e inn-rp n -tati on fo r ench of tln- f(l llt l1.\i n~ Ih t't lphyll illt' ("tlll(1.· nt mtiu llS, u h laillt'tl ill Illrt 't, d ifTt'rt'nl adult patu-uts dlirill V; a n in fusio n o f ;u nillop hy llillt, a l a lu ns tallt mi l' o f 'Pi lIlv;fhrllv;. :Xu Iht 't Jp hyllillt' W ,l-' p rc. 'S(' lIt in Ilw hCM: ly lit tilt' st art o f tilt' infusion. In yo ur in te'rpn't al ions ind nt!t' lM: llh a l'tl m parisc lll o f o h\(' I'\"('t1 and t" I:N't.1t't l pl;I-\ lIlli t"t JIII1.'n t m t i(ms a nd a n t'sl imatioll o f tilt' \'a llltoso f d t'ar, UI("t' alit! half-lift' in t'lIl'lI pa til'nt . '-\ SSlll llt' Ih at tilt' H IIUlIlt, o f tl ht rilmlinn (lj ft'rJk~) is tilt' SlUl\t' in all thrt't, p at it"llls a m i Ih a l t llt'Y a n' lJC m s lllokin~. ht 'il1thy ad u lt... t" ('('pt fo r Iht'ir ;l\ l lu n al it' ("t )l\t!iliClIl. TOW CA ~
P" lf"'l
, I
3
lI>oo.n _"""""'1
3 16
30
I'V&'M IHfOPH'o'UNf C(lr'-C £N1.....1lQN
1""91\J
35 18 6
CHAPTU 18
5 . Mr. ,".J. i",
U
70-1.:~. f)'~" l·ll r ..o ld u ",th m utk llalit'nt "''''ith t"lJU~l, ..th l· cu n litu." Iall-
ure .He i....tarted on llm ino l)h, lIine Illh ld.. orally a nd hn'" 1l 1)lll"'lIIll llll'·n p l., 'lIillt.. cnn~'nlrnti on mea..u rcd a .. noted in T able 11t-."i, Il l' ",nlOl.l·'" 2 pill'll." of ci~a reues
... J-
M
d ll" ,
.
1Wf WHENI'V.Y,O,A ~ lSOIl' "","",OM
"
'
J_ 2
1800
14
22 00
'"
8 00 1200
10
"
1800
PIosmo $ample 00I0,r«! C-18mg/1
~Al
0051: I"'{II
400 200 300 300
a . E",li malt · tln- \~tI Ul '''' Ill' d ,'am llt't·. volunu- Ill' di \lrihuliulI . alltl half· lifi- t·\pt"l·lt-d fur tllt"llphyl1int· ill Ihi'" patn-nt . h . Est imatt· lilt" t'lIIt" 'IIlra tioll (,'[M'dt...1at III(' timt' of sm ll p l i ll ~. c. Cmnpan' tilt' llh~ · I'"'''t ... 1and t·",limatt..l concr-ntmttons. d. Stall' w"i{·h pamll1t·!t·!"'i y' lll thilli. IIt"l... 1 to 110.' rt",i ~ ...1 am i hy how mILl'll In ;U"'ltllli for am' di lTt·n:·m ..·IIO.·hn...-u 1)1)\('1'\"(...1 and {·s lilllall... 1 (, mt1·lll mlitm",. f). ~(r, D ,\'·". a r.H' , 'l·" r -o ld . 7".L.~. a lco ho lic, l·p ilt.·I)tie l),ltlic n t. h a ", been ta L.ill"; phl·noharhih. 1 (2(M) IU"; at bedtbue } fu r 3 , e lln. lie lu"" been Free of ~' b un'" for HI Il'a ",1 1 , 'c ur. lie lIt1miHlod 10 the ho,,"pilal 011 Ja n ua ry' 10 " ilh a hu. iH and general cemral n en nu", ",)·..tern dep re..",ion. without KIt."I.hol on h i", hn·Kth. A p la sme phl'noharh i ta l cnl1~'nl nalion o f 51) m Wl- wa ", nu.·a ..ured in a hlot"1 sam p le drawn at I I :Of) of th a t tla , '. nil' tlru~ you" discontinued (i n el u d i n ~ no dO"l' 011 Jllmuu." 10). a nd a no ll ll'r hlot"1 "'iImpll' Wit'" nhlltinl'l l un Jllnullry' 16 lit 10 :00 to determine if Ih e plltil'nt Wit.. metllholi zi n~ the lim", more ~.Iowl,· t ha n espected, a ", the IJ.ldil· ut hacl ..i~n", of h epatic C'irTIUl..j ",. nit, "l"("Imd concent ration wa", 16 mWI.. a. E\'aluah' tilt' d ata in tilt' ~ 'l jl lt' ll tial lll a ll llt ' r rt"tltlt's!t"'! in probk-m 5 . h. ( ;i\l' 1l Ih" l d" ,m Ult"l' is tuut-]! mon- variahlt· tha n \ll lUIIIl' uf t1istrihuliun (T" hlt· 1:1--2), ",talt· tilt' li}.:" I" {~Il l~' Ilf 11 11' Ilb~ 'I'\·lIliOlI'" 11M' I,· ami prm;t1t· a n "'''llllltllt'mblilill for hi", future ituti t·pilt·plit..· tllt'mpy with plwlIllharhital. r • ~h . K.I>•• a 10-1.:,;. &I-'l·a r . .o ld we.. adm itted to the hm'l)il a l a t 13 :30 nil April n ht.'<-"UU"l· of "'hol1nl·.... of hn'nth lind \\hl'l'7.in~, ('.on~l·",t h l· C'llrdillC' fa il ure a nd a ..lhma Wl'n' confirmed h,· clinica l "" m p to m .., To tn'a t tilt, Il..thma, ",hl' WII'" nd rnini "'len'
"'Il.'"
Section V
SELECTED TOPICS
· :
19
DISTRIBUTION KINETICS
OIJlCTIVIS The reodel' will be able 10: I $late why the oeecoeponeeot model is sometimes inadequate ro descnbe kinetic evenl$ within the body. 2 . Compare !he scm olrwo escceenscls wirh the compartment model lor leprMel'lling pImmo concentJolion dolo showing dislribuhon kinetics , 3 . E~imole clearance and the holf~ile 01 the phose ossooced with the mojoflly 01 e1iminotlOO gMtn plasma concenlrali()n-lime dota 01 a drug showing distribution lineta. 4 , Define 000 8slimofe the distfloollOO pc-ceeers: ,nilial diluliOn volume lV,1. volume during the terminal phose IV), ood volume 01 disll'iburion 01 sleOOy slale IVJ. 5.
Describe the impocl cl disll'ib..lion hme 0010
kine/ics on
the
inlerptetotion
of plasma
concentratIOn"
follov.-ing administration 01 a Single dose.
6. E-.pIoin the inRuence of distribution kinetics and duration 01 odminiSlfolion on the tilT'le" COUl1e$ of eeeeeeeceeo in pIo$lTlO and amount in ussce during and ofler stopping a cooslont1ole infusion.
7 Descnbe how dislribuliOfl kinelo ,nRuences the Ruetvotions of p1asmo and lissue Ieveb with lime during a mulriple-dose regimen . 8 . Explain how dislribulion kinetics con inRuence the interpretation lime dolo and Iefmincl half·Me when clearance is cnered
of pImma concenlrolion"
TIlt" first fuur sect ions cover mo sl of tilt' Iundunn-utals o f pharmaco km ct jcs. Section Fin ' 110 ..... exp ands on ~ lt"l1t'(l topi('S: it l)('!Q lls wnh chapters 0 11 dut nbut ion kine tics lind pburm'll."lllo¢c "-'SpOIl<;(', Su b<;('ll lll·nt chapters deal ..\ith lI11'talxllitt· ki'll'tics . tiose anti tiuut1l'Pl·llllt·nd l·s. turnove r ("l)IJ('t' pts and tlialysis. T hese topics du nut h uild o n l·a(:1. utlll'r ll-S extcusivcly Il.\ do Illl' p n ....-ious topics . ~(Jta"ll' exception s to this stat e me nt art:' fOllnd in ap plica tion s o f dis tribution kin et ic concepts in the chapters 111\ p h'lrJlIlll'llhlh'il' "-·sl)lm....·. turnover coucepes. anti di lll~'!i i s , Purt m~i n ~ the 1)lI(!y as a s i n~lt· ('llmpart lllt'ni is uppmprtate- for ('stablishing: 11ll' fU IllI'Imen tal prin ci ples o f phanuacokincncs bill is ;111 inaccurate re presentation uf t....ents Ihal follow d rug udmfubtratlou. A I ~l-\ k' assumption o f lilt" l'(llIn'pl of a one-compa rt ment n 'pn-sentuho n of di stribution is that equilibranon of dOl~ between ttssues and hll)lI(! II('\'u rs spullla llt'lJllsly. I II (('ali!)-'. dtst rtbnuou lakt·s tune. 111l' time- required depends 0 11 tissiuI)(·rfusioll , I)(' mll'ahilil)' characn-rtstlcs of liss\It· membranes for dmg:. and its partitiolli ll ~ 1)('1\\'1 '('11 tissues am i blood (C hap. 10). lj.,trIo rin,gdi stribution kim-tics is n.·a.';oua blt· ...., lo ll,g a.s tILl' error incurn-d is al'('(·ptahl(-. Th is error la -couu-s un:w('t.· ptahll· when Ihl' (JIIt' -<''l''lIpartmout represcntanon fails Iu adl'( lualdy e xplain uh ....-rvurious foUowin/ot t1 m~ atl millis· 313
".
OlSTillllJTlON
(l-W'TEi IQ
'TICS
tra lion; tll( ' f(' is a { lall~('r o f S i~lifk'all l mis iuterpn-tation of tlu - nhSt: r" atio!ls; and major di scn-pancies rx'eu r i ll tilt· (-'l Je ulalioll of dnl~ t1osa~e . slid , sit uations a rc most Iil.:d y 10 a rio;(' whe-n ('i t l wf substantial " IIlI UlIl ! S an' chminntedor « 'SpO Ils(' O(:l:Urs before di strihution equilibrnuu is ad li("\'t'(1. Thts d laph' r deals wit h the pharmacokuu-tic n lllW( l lIl ' llt't' of di stnhutiou knu-tk-s. TIlt' 11I11)
EVIDENCE OF DISTRIBUTION KINETICS E, idt,!It't, of t1istrilm!iun kindit's is IIsually inferred (m ill an early rap id ch-clhn - in p];lsm a (h lclIMll ('U lI( 't 'lll ral io li (oUtl\\; u j,t an i s . bolu s d oS(' ; \\"1lt"1I littll' d m ~ has be en elim ina ted ,
am i fro m tilt' ra pid o nst't a mi t1t'(:lilJ(' in Ihe pharll\;ll·oloJ.~il- t,lTt'<.1 of sonn- dnlhry> d UrillP; Ihis ..arly phase. Dal a in Fip;. 19-1 , which show tjn- rmu-ent runou of thtopc-ntal in various ussue-s aflN un i.v. ho llis d ust, IIf this preoperative p;(' Ilt'ral ,t!ll'slhdk to a t!op;, I)m..ide din-ct ('\i tlt'lll't' of d istribulion ki m -t ics . Thiopental is u sm all, h i~h ly lipid , sc,lublt' t1 n lp; for whkh d ist rih llliOlI in tn t'sw nti nol 11('(1'11 I'stahlisllt"tl. Ana.l)'Sis of the sitn atio n Indtcat es that th is does nol occu r for SC,,\'('ml lllon ' hours. at which tune tilt' lIlajority of thiopental n'maini ng is in fat. RI'<.·all: TIlt' WI'alt'r til(' 1),;lrti liol\ of a d m g illto fal, (I T into ,lll~' tiSSU(' , the longt'r is t il l ' lillll' required 10 ad lil'\'t" dt srn buuon e-quilibri um (Chap. 10). 1I1J\\'l;' \'l;' r, nnly if the ap -
-a."
§. c 0
100
50
•\
~ ~
Fat
•
u
c 0
;;; c
Muscle
'--==
~
~
0
"
Liver
--------==:::
'-'
•
Plasma
~
6
0
2
3.5
3
Hours
"I..
19- 1. ...·u" I....:-ontl""I(· 1'''14 " f tI..• e'''' I(~'U( rail" " .,( tl,i"I',·" t.J ill "",;. " " 11\_""" "".1 <m" (e~ "' ,n..1 lir...) "n i ,·, 1..,1,.. ,Ie...• " f 2.') "'''''''II: In " ,1.11(. :\. 0(.' tl..· ,~..~ ';
f,~1. ",-j,,~
CHAP1E R rv
DlS1R18UTION 1(lNf1l(S
31S
pa n 'nl ' "olumt' of di slribulion of a lissnl' (}\." . \ 'r ) is a major fmd iclll of tlw total volmne u f tlislrihutioll tluc's IIplakl' Into that tiSMW suhstantially afTrt1: (' W il ls wtthln plasma. With thiopt -ntill. whk-h I. 'l~ an atl ipmt '.It )-p lll~ lU
INTRAVENOUS BOLUS DOSE
Presentation af Data Sum of EXIMllll"n t ia l Terms. TIlt" t'arly rapid and subsequent s1m..,.r t1t'('lillt' in tln1'I.lsma {"( lIlt"l'nlralion o f axpiriu in an imlhi dn al slIbjt'(1: follos' ing a f).')O-mg l.v. bolu s tloS(" (Fig. 19-2) is t~lli(";ll of many dnt~s , Had uo s amples 11t't'n taken dllri ll ~ tilt' fin-t 10 m in, tilt' n-munalltm-ar d,'("liTW of till' ph sma eonceutratinu when plot ted on \(·milugarith mit· ~ra p l. pap!"r would ha \"(' lx-eu cha ract eri zed by a mnuoexponential equation. and onel'Ulllpa rt llwllt d is!lt)sit ioll ehar.tt"!t' rislil'S would ha" " bee n apphcd to asp irin. Rl'l..t1I: The llltlll(It'\ !ltlllt'uti ,,! t" lliatio n is (;(0 ) 't, -b, when- k is tile rate consta nt with an assudalt'tl half-lift', gin-II hy o .69:lIk , alltl (;( 0 ) is till" ant icipated initial pl'lSlllil d rug conc entration. ~ \"I"n us tilt' iult'n:"pt nil tilt' plasma concentration axis ",11t'1l the line is ext rapola ted b ack tu ttnu - I.NO . Fur aspiri n k is {) .o.')() m in - I, tilt' l'Clfn'sf>l. lIId ing hal l- life is 1-1 min , am i (;( 0 ) is 3.1 mWI.. C:()i ll~ further. tIlt' \Ulu nlt' uf drstnbunon [[){)S('/C(Ol] is 20 L anti clearance (I.. . \ ') is ().~ I/Illill. Xotit'C , th at tln- t';lrly pt.lsnm tUllt'l'lltmtions lin' higlwr than those anti cipated hy ha('k t'xtr;llltliat ion of tilt' tenniual slolX' urn ] th at tht' earlie r the tiun-, the grt"illt' r is tilt' di ffereuce. \ \1It'l\ ti lt' d iITt'n-lIl, " al t·'Il,.. I, sample nnn- is pluth 'll 01 1 Ihe salllt' gr aph. 0111 1111.' tlifTt'fl'lIt'l' \"ulnt's f,,11 till auuther sl mi~h t line , which ca n he characn-nzed hy " 1Il 0 1lC1t' X'
Hit. 19-2.
·· ., ··, , ,
...·mi l"ptitlnll it-..J~".
' 'WI--
(--- ) \ I .5..511 ),1l. (R... lra"'l' (rum R" ",t.,..I. ),1 . a... 1 Hit,.,4man, S.: 1'I'am"....ld ' lt 1i<... Ill".'tot;oi . "']~ii<' a" d sallt., ii<' "" d ..rlo' r inl ra.. '.".,,~ ...1_
.,.1
m ;nhtl>llitlt' in mal]_ J- 1'I". n n Sli . 5:":1313- 1319.
\ G;e - ~Jl
..
I!«>'t.)
/~.
o
,ji'l'la~1 ...1
fi,,'j() m!t I" a .ul>jt'(1. n .., .l.'(~il '" ill , ... I('t'l'Ir-..lit"l ((...."....1I"linh ) . ..11 I,..dlar-......"ti,,,l lo;.' tI,,· .um cor I,." ..'I" ....."liltI h'm.., C ,r - ~ I' 1•••• 1al lt l C~ - ""
",\. \'''1
G1e - ~ , I
\\110·"
tl.., raJ l ill II... 1',,",111,;1. n ll" 't'ulrltIi" " "f ;Bpi ri" i. iniIiall~· I"lIpi.t h.ll Ih.·" s1o...., aflo" all i.v. 1".1.., .1..... ur
\
. 20
40 Minutes
60
316
OWTE i lQ
D1SmlUTJON I(INETICS
(lIiIlI'uti,,1 t'
'1/2
fi j
lllWI..
Bt'(,UlS(' all tilt" plasma concentranons at tilt' later tunes ("lU I 1)(· fiUt '!;II') ' one equation, G(0 1f' - lr a nd h"'{',IlIs(' a t Ihr- earlier tunes. all tilt' di ffert'lll't' values can 1)(· fill('(1hy allotlwr l'flll
C - 8(Ole - '" + qOle- t ,
=
For (''(a mplc>, tilt' h it' xpo lll' lIlia ll'(jllalio n C fii'c, -U 2.1r + 31.· - uc"",. , WIWH' t is thl H.' in minuu-s. ad c"IIIlOlIt· ly t1c' MTiht ' s till' d c'(.'lillt· in tht· pL,sma aspt nn (''OIlI '(' n t mtio !l follo..\in~ a fi.5U- IlI~ holus do...-. SOllwIi IlIl"S. when lISi n~ this difTe n ·lJ("t· p r oced ure. 1:1I0\\1l commonly ,l~ llit' lIu 1/'ot! (If n ',dl llUlk a slim of three and ol't'iLsiollally four esponennal te n us is n 'quin-dto ad ('t lua h ·l)' fil tln- nh...·.....a-d coucentranou-nnu- dat a. SiUl't' III(' pri ll(.iplt'5 in appma('hin~ Sil l'll data an" tln- s.:IIIW us those usedto aual~7.t· and Interpret I··..onts dt "l'ril x'tl h)' a hil·xlllllll'ntial l'(lllati on . 0 111)' tht' simpler {'il>;(' is ('tlllsidt' f('t i further ill Ilris hook. Tn fad litall' th l' di M'llssioll a more uniform '....1of s\l l1lxlls is lll'('(I(.'(1. Hur ln-r than us i ll~ IIII' difTI"f('1l1 S~l11bols u um ] k, tilt· ~l'III· n d s)'mixli j. is uS('(! to dellole till' 1·.' Jlllllt·nli,,1 ux·fTidt·1l1. TIlliS, Etl . I rau he rew ritten
,I.'
2 when- the sllbM'ripts I and 2 n-fer to til{' first ami Sl't.'tllld exponential te n us fl'slx'(1ivl'1y, am i C. and C 2 refer to tilt' l't l rrl'sllll ll( li ll ~ ze-ro-time- interce-pts, or l't x~ fTid('n ts. 8)' couvenlion . IIU' exponentialterms an' amUl~('( 1 ill dl't.·n·a.,iu~ onk-r o f A. For example. in Ihe case o f aspi rin C I = 6. IIIWi-. A. = U.2.1I11in - ., C 2 = 3.1 ul/dl... ;lIId A:z = O.l).')() min - I . \\'ilh as piri n . 1\\1) l'xIXl!Il'llti
D1STRIBUTON KINETICS
CHAPTER lQ
31 7
clearly evide nt on co mparing the fall in plasma aspiri n concentration in the ea rlier mom ents wit h the decline of th e first expo ne ntial term. A Co m pa rtmen tal Model. Although for the majority of situations in pharmacokinetics the des ired info rmation ca n be obtai ned directly from modificatio n o f Eq. 2, it is sometimes co nce ptually helpful to represent dispositio n pictorially. Figure 19-3. a tui o-compartmcnt model, is a co mmon form of such a representation . Compa rt ment 1. the initial dil ution volu me men tion ed above, is also frequently celled the ce ntral co mpartment because dm~ is ad ministered into and d istributed from it. As mentioned, the initial d ilution volu me o f aspirin is 6.5 1..; for many othe r drugs it is muc h large r. These values are clearly greater than the plasma volume , 3 L, and therefore this initial d ilu tion volume mus t be composed of additional space s into which drug distributes extremely rap idly. These spaces must be in well-perfused tissues . which probably include liver and kidneys, the majo r eliminating organs. Elimination is the refo re usually depicted as occurring directly and exclllsively from the ce ntral compartme nt. Drug dis tribu tes between this central compartme nt and a pe. rip he ral compartment, co mposed of tissues in to which d rug dist ribute s more slowly. Several poi nts are worth men tion ing he re . First, th e model is de fined by the data . The num be r ofcompartments or pools required equals the number ofexpone ntial terms needed to describe the plasma conce ntration-time data . Thus , a th ree -compartment model is needed whe n the da ta are best fitted by a triexpon ential equation . Next , the mode l depicted in Fig. 19-3, o r any other model for which drug eli mination is portrayed as occurring exclusively from the central co mpartment, is not unique. Three two-compartment models can adequately describe a biexponenhal plasm a concentration decay curve: the one de picted in Fig. 19-3, one wit h elimination occurring from bo th compartme nts. and one with loss occurring exclusive ly from th e peripheral compa rtment. No distinction be tween the se th ree possibilities can be made from plasma concentration-time data alo ne, and while the mod el de picted in Fig. 19-3 is the most favored one , based on such ph ysiologic co nside rations as th e initi al dilution vo lu me exceeding the plasma volume , e lim ination ca n some times occu r in tissues of the peripheral co mpa rt ment. Moreove r, occas ionally the live r (o r kidn eys ) is not part of th e ce ntral co mpartme nt. For example, the initial d ilution vo lu me of ind ocyanine green, a dye used as a dyn amic tes t of hepatic fun ction . is only 3 L, the plasma volum e . T he major perip heral tissue . in this instance the liver, is also the pri mary site of elimination via biliary excretion. A two -co mpartme nt model, with elimination occurri ng only from the peri phe ral co mpartment, ther efore best describes the disposition kineti cs o f this dye. Last, d rug d istrib ution within a compartme nt is not hom oge no us. Altho ugh the concentrations of drug within and among such tissues usually vary enor-
~
0 l k" Elimination
k" ~
k"
Fi g . 19-3. A two- com pa rt ment mode l of the hody. Drug is admtmstercd into and ..limiuat..d from compartment 1 and d istri blJk~ h.,I\Wt·n compartme nts I and 2. TIle rate t't)l "tan t~ f"r the processes are indicated.
311
CHAPTE f IQ
D1STfrBl/OC)N KINETICS
IIIl11lsty. tissuc", an- 11I1lIpc'(! h '!-:{·tlw r int o it compartun-ut h t '(".III S(' til(' nun-s to ;It:h i("\'(' di sl rilml ioll ("
('UlIlp'U1lJll'l1t
p n K1'SS . TIlt' (;.111' ('u mla nt lo w is ;Lsso d alt'(! 'lith los s of d n lg fmlll (,( llll lla rtllll'lI l I hy metabolism aml r-wretion . 111( ' uutt (If all th n -e mit' coustauts is reci procalumo. Hate equations t-an 1)(' writte n for 11I0\"(' 1111' 111 uf amou nts Iwhoo't'('11 tilt" ( ,(l lllpmt lllt'll l s and fur dnl~ l'iimi lliltiuli. F()I1I1\\ill ~ an Lv. holu s duS!.' till'S(' r-quations an.' Role of change '"' of a mount of drug in compo rtment 1 Role of movement from compo rtment to comportment 2
Rate o f eliminotion
Rate of change "" of amoun t of drug in comportmen t 2 Rote of movement from compo rtment 1 10compo rtmenl 2
Role of movemenl from comportment to comportment 1
4
2
5
Rate of movement from co mportmen t 2 10 comportment 1
wlll 'n' A l uml i \;l an.' tln- amounts of d m g tn cenupart meu ts I alll12 , rl' spt'l1:i\"dy. In!l'g ra lio n of tilt' s!' run- l'fillations Im " idt' s a hit'xpO!lt'lItial''flnatin ll, of till' sa u l(" form ,IS El l' 2, (or Ill(' dt·di ,l(' o f dmg (mill plasma, ('Xl'f'pl thut tln- (1)(·ffid ,'nls am i , 'xl")(lIw nls lin' recast in It'fl ll S Ilf til,' parunn-ters , Il ·fi ning III(' compart mental mo d el. EIllli\"alt'nl n-lationshlps behn'f,'11 thr- h i!'xpulIl' lIlial am i " \'O-{'fIIl1p
r
,
(
part
,.
I~.I••I...,
M ....I.·
........ahl,......_ ........ 11. . . . . . . . . . 1.... rw.·
. (_21 [~ V, 1i.2
PIo!o/TlO ccoceorronce
IQ
- ;',1] e.' "
-+-
'
1/21l_,]
-+-
' 2'
-+-
1
[ ~ . [.1: 2' - ;' 21 e - ' . V, (i., - i.21 .1: , 01
-+-
, ll ' 2 ... l 21 + .1: ,01' - 4 ' 21.1: ,01 -+- ' 21 -+- .1: , 01 -
Inll_,]
, [-,2 -+- ' 21
Ceoooce tell hllol d ,lul,on -..clu me [V,I Volume cJ d'SIf' buf,on IV] d uro ng \e<m,na l phose [V] Volume cJ d,s/f'bvtoon 01
sleOdy
~Ie
[V.,I
'< ,
'< ]
i. ,
]
.1: ' 2
""",/(C
+
S)
Dose/IC,
-+-
C2 )
"' 1 . .]
ClI;']
""'" [¥t
.
[C, +
+
~1
S I' "
-+-
.1: ,01' - 4'2).1: 101 .1:] , -+-
-+-
'2' . ' ,0 V, .
'10
-'0
". A ltlloll~1J l'xp n~..ill ~ (Llta ill !t'TIIlS of a ('u m p;u"tlllt'lIla l lllllclc" and a.~\lJ(iilh'( I I'/;lr. lll l(' ll' ~ milY a ppc'a r 10 ¢n' J'rl'a h-r i nsi~hl into til t· data, caution sho uld ht' t'w n;i M"'l1 in t1oill~ MI. HI'IIl C'IIl!M'r that the cotupart nu-ntal mudd c how-n is " flt'll not 1111111111', alltl Ulil' (';.Ill rotn ·ly ll..s i~ l a physiml or phy"iolu¢ c' nlt'allill~ 10 ti ll' vnhn- o r lUly Hf til(' mh' (1lllsfanls . Accordi ll~ly. 11111('1. of ti ll" SlIhM't I" c' n l di M"1lssioll is n-l..ted to CII'M'rihi llJ.: dOl I-: di slx )Sitiu li ' ';'" till' sum of ('llpullt' nlia k II0w(,\'(' r. phanniK1,kinl"fit· o h"'t' rYal iolls a n' di M1IS"t"t1 in h-rms 11 11' {'UlIl jlMt llw ll lal lllo cll" WIIC' Il th is p R IC:'( 't llm' fad lila lt'!i ~( · l lt' mll ll ll ll'f'i la ll( li l1J.:.
ur
PltamcKokineti< Pororntten C IC'K rn m.'t.". Elimina tio n IIl'\'1' " at all !iII it'S . Ju st i tS pla \lllll {'1l11l'(' nfmt iull is hiJ.:llt'st im lll('(lialt'ly foll( J\\in~ an illtmw llOUS hol liS tllN ', so is mit· of ehnuuarion (e I. ' C ), Sill... st'l lllt·ntly. bot h plolsllllt ("Ilnl"l'nt nltiou all( !("Ilm"'polltlin ~ rate nf ,·lim inaliull fall mpitlly, To (,;tk'u1a t,· 11ll' amount di mina!t'11 ill a s mall uuil of Ii uu-, tit, n'1, 11I that
Amount eliminated within interval dt - Clearance ' C · dl
6
when- C • tit is IIII' l"llrrl'Sjltllldinl-: sma ll a n-a under 11u- ptLslJ\a ("I Ill("I'lIlnllion-linw ('u rn ' wi lhi n lIlt' in h-r...a l tit . TIlt' 10t;11 amoullt t'l imi llah "ll. tln- tin...• admiuiste-n-d. is tt. t' MIlIl of all tilt' s mall amoun ts ,·limin;IIt"l 1 from tiull' ".t'Ol lu tilllt· infinily. Tl u-n-Ion-, Dose - Clearance ' AUC
7
wlu-re A t 'G is tilt· tottl1 a n 'a under till" phslna d OlIl: t"I lIK"I'u tmtillll-li nlt" r-urvr-. '\ I"I"Iln !i n !tl~" ll-S wnh till' stmpler 1l1ll'-("I1111 jl;,lrtIlWllt Illtll!l'1.d" a mll("I' (C I .) is IIlllst n 'atliIY" slim a!t'11
hy dhidin~ Dt N' h)"" t 'C, 111l'an-a lIlil~·I ll.· dl'l" nnilll'l;! [rmu till' tmjll.·..~ lidal 011,· (App" lIl1i, I- A) or . mo n - ('u llw nit'nlly, hy n'al i 7j ll ~ th ai tln- tol al art-a Ulldt 'r1~in~ "aell t'\jltmt'uli al n-rm is tll(' n ·Ol- lilllt· inh' I"(" pl dhi dt'l;l h}' ih (:nrrl'spond i n~ t" llt lllt'lIlia l ('C",'fTi d " IIt. 11111S. lilt· 101;11 area nJrn'Spond i n~ 10 El l' 2 is ¢n'u I,:,'
AUC -
S i' l Area oisociolec! with initial te«n
+
f>
"
Area cssoected
8
will,
leit lerm
\\ 'la-n illst·rtinJ.: tt.,· apprnpri att' \,t lllt'S for IIu- il-spirill t· ~t m plt· into Ell . ~ . lile' \'lJ llt' of At 'C It-sstllialt'l;l ....i th tilt· 6."j( )- 1II~ IlIN ' is 95 1 1lI ~-lIl inl1 .. stl illat Iht'lol" l d t'a mllt."I' of 'I-spirin ill IIIl" indi\itlual i ~ 6.').1 m IJllli n, S oli l'C ' tlml dt·lImnl't· is conskk-rablv sma l er thau ti lt' val..t· (
'20
OWTU1Q
un til d istrihutiull t'i lllilih riUlll bt,iw("('u d m~ ill pJ.i.\Illd and all tesues is <1(' 11' ( '\1."1.1; this (It'('\I" durill( the- h-nninal pI.a....... OIlJ~' dWII dut"5 (Lt.·dillt· ill all ti....\ ut"§ parallel that ill plasma and is pn lpmtiollal i~' IJt'Nl"t'1l plasma concentration anti amount ill hudyachit"\l-d. 11... ".111111(' of tL\lrihution durin~ tl.t· tennmal pl........ ( \1 can lit" Olbktt."C1 as folk""" . I> n ri ll ~ rlu.. plla....• II", ('u ll('t-Il' r.lIin n is !ti\1"11 J~' CI' - l.Jt t Fi~. 19-2J. aJl(! C'om"'p "tdi nd~"
Amount of drug in body d uring .. V · C • V · C2& terminal
9
;2'
pna:r.e
IIt"lwt " t':dmpCllat iTl ~ Il;.ll..k 10 tinw ze ro , \ • . C: rum! lot· ti ll' amount ,..-('(It''(l lo ~\l' a p L...\III;l ("Il11("l'ul m holl of C2• hat! (ImJ!; sp(l ntallt,() II\I~ ' distrilmlt'l;l into ,lit" \'Ollllllt'. " . 111(' amuunt ,
, ' . C t _ remains In ht" {~.tI<:\l lah"( 1. \ \ l w ll plat't'tl into till" lu ly. tlw amount, \' . C2• is
t U;lIl~' lIlatdl('t1 by lUI ('(I"a1 amount t'liminah '(t is tll(' pneluct of dt'll r.lI\(1· and area . and a\ C2
('\l ' n -
As tln- amount n 'mainillJ: 10 h(' t'liminah'tl 1A: is IIII' il-ssu d a h "'t! an-a, it ro ll uwli that
CL ' ~ i,
Amou nl in
Amount remaining
body
"be
10
e1imincled
'"
-
V
VDtumeof distribution
Ct i,
11
Total deora nce Terminal ellJl'O'*1tiol coefficient
6
A
100
~
v
30
c .2 0
.sc; 10
~,
,
~,...,
~
0
E
-e:
1
~20 c
0
6
12
Hours
16
'"
6
°10
'v,
~
E ~ <5
>
24
fi.u.....O(.,...
0
0
6
12
Hours
16
24
flit, 19--4 . s.-.~ ....... h 'l(o" i .,,", .... " ..~d._. .-l. . I ~ ... ,,( d"'Il:frtl... ,.... Hul'&l d1hrtlnn .,.ft..... ,,(...md. ~ma it • J-1 . iI 10 .... "'h mmlRahon (",," I I(~' -.I d1otnhut.>n in to I.... nwIn' drMfy "'I"'h. hnhO( ""'un n... fall In ,nt of drur: in I ~ io thrrrf lIutW~ h tlwJ !hr faD in t.... am""nt in ,.... ,nm..J d11"hr'" •.-.Iu.... ( ~' ''fw.n d1otnt.uhon ,wlil>n um h&.'",,", .il rd do Ihr drd.~ ,n , ."..,..nh in I.... IOmai d1hlt.'" .d" .... .".1 in ~ma ~ /umr "''f'''') t h..t i" I ~ . ." . n-flo"l'tl~ II ~rnll. It.apr;arrnl ..,Iu (i dtot:nhuIIlIn (A,IC ). ..hid! ju( If. ."... f'<1""" lho- in il'&l d1luhr'" ....aUITM' (\'1 ). ,..""'..._ .."IIh I" "l'P".....-f..fIll:. h,,,,,,..,; .-.1... (\1. .. hid. .u"n .. flnI (holnhubun ""lwllhn um it . -h........l
( HAPTH
rv
33.
H('l tlming 10 tilt' example of aspirin, CI. = 6.').l l1l l /min and ~ = 0.0.'50 mi n - I. Ilwn.'fon.· its volume of d istrih ution is 13 .i L That is, if during the terminal phase- tilt' plasma l1111ce ntratton is 10 1Ilw'L- then the amount in ti lt' hody is 137 m ~. Sinct· 65 Ill~ (10 mlifl. X 6.5 L) an' in tilt' initial dilut ion volume. tln- f('Tllaill ill~ i l 1Il~ mu st 1)(· in the tisSlll's with w hich aspi rtu slo.....ly equjhb rates . A compartsou of Ell. I I ....ith Ilw one that has lxx-u used in all previous c hap ters II) define the- volume of dislrihutio n ( V = Cllld shows tlWIII to he the sa me , n't.'( lj.,lJIi7jn ~ ti ll' ('fI',h'lllt" K't' o f k ami A~ , Iht' n-nmnal expom-utiul coefflcteut . TIll' reno \'1I\' ~ \'('s an es timate uf tlU' dt~'t, of e rro r in p redicttug tilt' iuili,ll pla.~ lIIa concentratio n lIsin ~ a on e-t.'IllllpMtm(·nt model. For e xample. for aspirin. ....i th \11111t·S for \'1 and \' of 6,5 and 13.'j L. n.ospt't.1in ,ly, tilt' error in pn'llil1:illF; initial con cent rations fr om the plasma couce-nt ration -ttme data dllrin~ III(' le nninal phase can IX" n..lativt'1)· largt" Tilt' emir ca n IX" ewn larger when pn'l lil1: ill~ comhtious ht")u nd the measured final p h;l"t, if a still slower nne exists. T his la..1 e rror is o nly o f co ncern if there is an app n'l:i,I" Il' accu mul anou o f dm ~ in this phase dllrin~ chronic admnustration . a point <'111lsidt'f("t1 snbSt·ll'lt'ntl.y in thi s chapter.
Distn'butio. IOnetks and llimination DlIrill J' the initial r.lpidl)· dt't.·li lli n~ phase, mon- r-hmtnatton oc curs than would han ' hl ~ ' n t'xl')('t.1:t"t1 had d istribution I)("('n spllnlallt"t)lls. Addi tion .u elimination is d ill.' to Ill(' partieularl)" hiJ'h concentrations of t1mg p n -se-nted to tlrv:allS of clinuuatton d u ring th is pi-nod. For IIl;Uly dmgs this iu<,'n-a-"t'ti t·liminatin!l is smal l und. ....'ith n 'Spt't.1 to elimination, \it.....i ng Illt Ill)(ly as a single <.1l1npa rt nlt' nt is adt~ l nak, For othe r dru gs. the addi tioual elimlnution represents a major [ruct ion of tilt, adlll inbh'rl"t! doSl.', and appmxi m at i n ~ th(· kint°li<.'S \\ilh a one-compartment IlIiKIl'1 is iuuppropnate. Area conskh-ratlons are iI h'l-~ is for makin~ tlus dectsiou. Rec all fmm Eq. 9 that eluninatton wisot.'iaft"t! wit h IIIl" coucentranons dl'fillt'tl hy IIII.' t erminal exponeuttal term, C ( , - ),11, ~ \"t's un amount equal to Cl..' C 2 "-1. ExpTt'ssin ~ tllb amou nt as a fr.l<.1:ion. f 2' of I~I.' admi ubh'Tt'(1 tlUSt' and ut iliri ng Iht, relation ship in Ell. S O
~ n's
Fracti on of eliminalion c ssccioted w ith lo ~1 expcnenticlterm
, _ C2 f;. 2 , AUC
12
Till' n-maiuing fr.l<.1:io n.j" mu st tl ll'n 'fon ' hawl x-en l'1iminal t'l l as a result uf conci-utrulions alx)\"(' IhoS(' I'XI)('t.1:('t1 hal l spll" tm ll~ lu s d istri bution occurred , i.e ., those coue eu trutions dl'fill('{1 hy C l Ot. - ),, 1, A ppl)i n~ EII_12 1u tln- <'1l-'i(' of aspirin. di mination o f 69% of the l lt ~' ts ,l-'i MKi ah"t1\\i lll th e tenulnul slol')('; IIIl' n.'mailling 3 1% tllt'n 'flln ' mu st ht, assoctan-d wnh plasma <.1J1ll't'II· tnmons allll\"l· thu S(' eXI)('t.1:l"t1h"d sIXllIlml("tllls d istribution OC"l'U fTl'I.1. Al.thulIgh d islri hut ioll kim't il'S ea nllot he i~ IOn.'t1, till" majority o f ll"pirin ('lilllinalion is d e arl)' 'l-'i SofJl.i a!t"t1 \\i lll ewnts d l'finl."tl hy thl.' h' nninal p ha.w , wh it.'h h,l-" a half-life of 14 min. Ba'il'tl 01 1 Iht· samt' f(·
322
CHAPTER 19
AMath.mati
difh-reut ra te constants , ),. ;uu! ~ . till')' hil\ \' d iITt'n'nt \1I11II.lI's of db t ribunou, w t.i<.'h an ' ~\l.· n hy CIA. ali(I CIA 2• n 'sfll 't1iwly. To eomplete- 111I' analysis . tilt' tln....·s of t ht· hn 'M lthetk-al d nJ~s an.' needed . TI)t~· an.' u hlaillt"tl [nun an-a l"l lll,idt'r'lttio ll' ,l\ fn llllw" . Si lll't· dose is the product of clearance and an-a. III(' n-spective t! US(,' S an.' CI. · (Clli••) and C I. · (CAl. Furt hermore Silll 't· CUG .!). . + C IJ-z. ) ("lllIals l l.(·lllial do....· "dminb l(·f("li. it [ulIllWli fnun E(I' 12 tllitl ! . · dn....• and! 2' diN' an' l ilt· 1,(lrn 's l'M Jlll li ll~ d o ....·". Ih ·)I("I·. tl utllial oh....-rvl"tll"llll('-·n lmlin n is W\l.·n h~'
. Dose e- l ll ICV~1 1 A lt holl~1J
'2'ICV;'21 Dose
e-
+
l2
'
13
tilt' aileI\'(' equation is a de-vi ce t ha t cannot , for (·x
("l llI i lihmli ll ~ tissues. it n·ad ily fll'nn ils l"itlculaHIl Il of (·\l.·II1s in
circurustances . :l\ suh...... j1lt'lltly Sh(1\\11.
(ON5TANT-RATIINFU510N Fi ~ lrt· 19-.'5 Illust ra te s till' lIlIlidpilh"l1 t'lTt"l.1 Hf clet nbunon killt'li<.'s OTI tilt' pl.l\ ma ct tn rentration UPOII stllpping u coustant -ra h- infusioll at \1In OIiS tilllt's a1l1nn ~ appmad l III plu-
. 'llt. 19-5. 1-:" .,,10 in pLa.. n\;l (u .I" l li".. ) ..,..I in .I
Ii.".... ( )
\ie,,,. tl..· I'I....." -
r - l " )_ r ~ l , ,_
..f...no ,_
Slowly Equilibrating Tissues
............... '..
.. Plasma
10
tI..• lim.. ..f, 1''1''1'':''1(tI..• infn," "'n..· la.t '''ll ldl.. 111 ('lUI 10.· ·nn d n,illl!: th,· nUllo. '·"' ''' k:. 1....1 (t:' l. 1.1). n ~ ..,.l1j "", f..r '....."'rlc-.
lIo.at / l • Coo ( 1 - r ~ l l ' ) ii,I..· n 'I ....tkJl' ..' tI..· .....I ..f tI ..· inf,t.ic,,, ;ll; I ith tI..· fin! r1......... ;u .. I.. ~ l ~_ i, tI..· .um"I Ii"1:f....
,-,
\
1
I \ \ \
,-,
,,
-,
,,
,,
0
,,
-, -,
-,
-, -,
0.1 6
. .
,-,
\
I I \
'(·" I ,...., " 1(1" ',, 1,>' C oo trl ( I + f J(I _ .. - l'·) _ r~ ""_ I .
is
i'1j( .. l lin ..· ' ,.....
100
-,
, -,
, -,
,
, -,
, -,
-, -,
-,
-, -,
, -,
,,
-, -,
, -,
, -,
, -,
,
12 Hours
,,
18
" ,,
, -,
, -,
-,
24
CHAPTE ~
IQ
DlST~IBlJTIC)N
KlNETlCS
n-au. At t 'a rl~' urues. a pronounced distrihution phase- is seeu upo n
333
st oppi ll ~ all infusion ,
because dtstrtbuuon eqruhbrium has yet to b(' achteved between drug in blood and thai in 1Il,IlIy tisSllt'S. \\'illl a mon- p mIOll~I '( 1 infusion, umre d n , ~ enters tilt' tissues. T Ilt' h 'llIlt'II('y u f dnl j.( 10 tnove- From bloo d to lissUt's is rln-n much rt>(II1('t>(1, and tht· distribution phase appl'a" l1Iut,h shal10\\'('T UpOIl stoppi llj.( lilt' lnfnslon. E\'('II al plat eau. !lO\\'(,\-t·r. SO!lW di strih lltioll lIlay still ht, St't'll upo n stoppi ll~ lilt" infusion . At plateau , rlu- mit's of drug ent ry into and o ut o f the lissm's art' t'flual. Upo n st(Jppi ll~ the in fusion, e liminatio n o f dnlg fmm pla_\l11a. alollj.( \\i th u SIlIlst.'IIIII'nt full ill plasma conce-ntration , en-are s a ~'md ien t fOT return o f d nl~ [rum lissues. Inilially, tilt' mil' of r-limlnanon fru m plasma ('X('('t>(L'i tln- rat e o f (·f1l m froru tissue-s. am i pl.LSll1a t'Olll'('lltm tioll falls rapid ly. Eventually. ho wew-r, Iht' ra te of ret urn fmlll till' tisSHt'S limits Ihl: mit' of c·liminalion from plasma. nit' hody then acts. om '(' a~aill . ,LS a si n~I(' (,(llllp
hents at PIaleau Pla teau Plas m a ('..o ll('{'lItnit io ll. T ilt' plate-au is n-ached when mit' o f d m J?: ellnunution
matches mil' o f infusion , Ii,!" Tln- plasma concentra tion . C... is thr-refon- n'allil)" gi\"t'n hy tilt' familial' equation
c _
RQ
...
Cleara nce
14
T hIlS, as lo tl ~ ,lS d t'a r;U1t't' is at1.'llI'ald y det e rmined , Ih(' rate of infusion I)('t'tlt'tllo produce a ~\"t't1 sh' ady-statt' eoncentnuion ca n be calculated. Conversely. clearance can ht'dt,tl'Tmillt'tl fmlll tilt' ("(JIIt'(:nlmtioll al slea d\"stalt' , \ 'o lu lI1I.' uf Dj\lrihuli on nt Sh" nd~: St nle . Although Iht' \u llllllt' o f di slrilm liolJ, V, Il Sl·fll ll~· n'lales amounl ill hody to pt lslIla ("OIlt't'lllrdtioll duri llJ?: th t' h 'l'lninal ph 'l'it.', its \1\1111' is iullllt'lIt'('(1 by {,lill1in;ltioll. As SI't'1i in Fi!?:. 19--6, tilt' fa~ le r a d m Jt is t'!imin ah'tl. the ~n'a tt'r is lilt' r.llin of tln l ~ ill slow ly t'fluilibm ting lis.'illt,S 10 that in plaslIIll d uring III(' h 'n llill,,1 ph'LSI.' am!' t11fr!·slxllld illgly. tilt' large r is tilt' appan.'nt \u lu lIlI.' o f d istrilmlioll. A Ilt't'tl, Ilw refnn '. ("isis til dl'filJ(' a \"(Jlulllt' l('flll to rt·He('f purely d islributioll. n lis \,o IUlllt' k rill applil's 10 sle ady ~tah' when d m ~ is infuSt'l.:1 al a ('(mstalll mtt'. T his \'tllullll' It'n ll. \'nlllml' d istri but ion at slt'ady ~tale , \ '••, is (\1'un{>(1 by Amount in body 01 steody stole Plasma concen tration 01 steady stole
15
CHAl'lt1l IQ
COIlCt1)tuaJi/.alioll u f tli is volume TlIay lx- Ilt"l pt'tl by tUllsi de ri n~ till' two-compartment 1II000Id dep il1t"(l ill Fi~. 19-3. At stt-ad)' slate, tile r ates at which d m~ enters am l lt'avt's ti lt' slowly t"'llIil ihrnti ll~ tiss\lt'S arc t'X.;lI.'t1y matelu-d. It then fellow s from Efl' 5 that tilt" amount in tilt' slow ly ~ '( I\l il i lmd i n~ compartment at stea dy stnte . A.. .2 is ~vt' n hy
A11,2 •
16
T ile amount in tilt' 1)()(ly al slt·mly state, 1\ .. . is till'
SIl IU
of A.. ,I and 1\ .. .2' Therefore,
17 Finally, as A...1 "" \ '1 • C.. and A.. "" V.. ' C.., it follows th ai
= VI [ I + ~J
VU
Volume 01 d istribYtion 0 1 steady stc te
18
In practice , as amount in the 1)()(ly l~.lII n{)t be de-termined physim lly, \ 'u is usually <:1I1culated fmm tile dispositiun pa r-tlllett·rs (C l , AI' C2 , a nd )-2) f()lIfJ\'; II~ i.v. bolus ad mi nis-
A
6
100
100 6100<1
.s'il. 10 ,
/
~
-
.s 10
Tissue
I I I
c 0
~
"
/
c
.g
c 0 <.>
---- -----
" ~
~
u
, - - --_! isslJe
~
I
u
c 0 <.>
1
-- -,
BlOOd
0.1
0.1 0
6
12 Hours
18
24
0
6
12
18
24
Hours
.'I~. 19-6. t:lilllin;otinu inlll.·l.~" ...tUUll" or.Ih lrihulio" .1" riujl. II.· l"nni,,;o! pl.,...... T" ;apl'n ...-i;,I.· d ,i. o.f;a!t"Ill""I. nlll,itll-r lhrdiltrillllliofl (J( 1I. 1Irul( ht1>.o~'f'1l 1>11.. 1(m I1l1I1t,. \ '8' 5 L) and II. him.. (m lum,·. \ 'r. 2u l. ), Furt llC'n lllJn ' , Irt "'" - I. .. , " ..I IIit' cc" . Tfll rolli,,,1' ill ,,;00.-1, n ''''l''' rt nlt' nl at "'lm],l,Ii"," ~n' rt l'...I if "" .,limi"ali"" ,,,-,'Un (;\1. 11... ".t"TlIt' of .ti-trilx,til", at ""I"ili l,rtu", i~ tilt'" 2.5 L. Wid, ..Iiminalio" of ,Inl~ lilt· ,,,,.'O ·nlr..litlC' in tilt' Ii~..... · (---J b !:"1..·I,ind 111.11 in 1.1.. -1( - - ) .tUrillg til(' t.. n nin,,1 ph.a,_,·, 111C·,,'1,:,' !Q\111l( Ii...· Ill . hi~lC'r "1'I"' n'1ll \..:Jut ' ..r ~, K. (8). C...........I'It·"I"'·. till" ;q>pan'n l ...tUlII" Hr c1t\ llih"liun ( \'8 + 1\ • \ 'r ' i< i'. -r,·.... ..J ;alit.... • th;al .."l......1,J'ti"....1o.r Inl(' t"jllilihli llm CC>ntlih ll. lI. \ '8 + K., . \'1' ,....,.
32S
fr..lion (Tab!., IH- I) . 'l1w in!t' r.n· b tiom hip' hdwl1t-u \ ".. '1 l1tl utlwr pll;IrII1.It" l illl ·! ll" par.u rwtN" .m- 1..'\ 1 IlIltl. ·"toocl (m ill IIII' 11lm " pl (If IIW'1Il n·,id.'lIu ' tillw ( :1..11' ::!·I. Tum".. tor ( :OIl (1 'p " , ,11111,\ PllI-Hili, I -I) ). 111l' \ ";I IIll " of v.. lit" IodWt"1I lilt" initial diluti ull \ H III IIl '" \ ' , . ;llIe l til" \1> 111111 " of lIi,!ri· huli"u durilll:: tl lO' k n nilloal ph ;l~ " v. III c:c'lw ra l. lilt" d iffc' rC'lIll ' l.du l l 'lI tlu- .. ;&1111"\ of \ '..
;ultl \ ' i .... mall. 'I lid l d"I" 'IMI, 1111 Ih.· di' I11 ...iliull l.jud i.... uf till ' .fnle:_11... t1iITN' ·Il.' - h b n:,·r. ,1"' l,.'T,·ato·r ,I... p\ h'lI l «f ,·lilll ill;t!i,," h.·fon· t1i' lrihutiuli ''' 'lIilihrill lll i\ .ll'!li'"\ n l T.. ;Ip p n '('b h- I ll i, 1.1'1 pc.ill t . (,ITI\j, It ' r thn ..· clmc:\. ;(\pinn. ~Ji(~ Ii(·.u:i<1. .IIII! c:,'nl.llllit-in, '11", t1i\j Mt'iitiull l illdit-v. Ilfln nali, .t'. 1 tn 'I 11In'l1l ~ j\ .I...III\ II.......· f"f.1 7n , " ~ \ llhjl ....1 M , ' .1'I" ri IL C H.7" II '" + .'i l.· l ..; ....llil... lii·,II-itl .C IO ,~ ,· - l ... + ~ '; I · U:'II ; ~'· lI t.ll l11d li . (" s 7.1 " U ~.) + ni l") •. _ UUI \\ It,· ~,· C i\ illllllV l. a llil li lll(' ill 11l1l1f'> . ~1l1 "'1lI 111i"1I of III.·...·
=
=
IlOlr.ulII·h-r \".1111'''' ililn th.· n p. 'I1i\t· ' ''III;IHfllI\ li\Il ..1 ill T ah'" I !J-I ~i. · ll k li ,r ;I_p irill. \ • .= 13.0 I ... \ '. . . lOA I .; fur , .Ilil...lil · ... i l!. \ . "" 10 .5 J.. \ '.. ::: I n.~ I.; a llllll,r ~1 ·1I 1 .lIl1il'ill . \ . = :\.1.3 I ... \ '•• '" .'jfi 1.. :'\lIt ;n ·. axpiriu and 'IaI;(~ li{·.Kid. 1I!.1llhc" \alll, .... n f \ '.. an- \ I'~ \ illlil.lT; IIII ~ .m· la" t l. •• il k p n .... I..llli ll.t!IIIY h"ulld 10 alluunin, am i ;M..... n lill~l~ IM\l' \111.111 \ulm lll'\ of dl \tn imliflll . Tle- ~n ·.I l< ·f \'aill" of \ . n ·I.II ~ ,' til \ '.. fo r .I\)Iinn ri........ 1.., ·.111...· ;IPIITt....i .lhl .· .·lilllill-lh"l1 lC / . :: ·11 I AIT I ' .." If'> I..-Ion- di \lrihllt icOll ''' llIilihriulII h .M',"it...,.. L for "'11ic.:7' lil' ,. i ll. tilt' , h lT" " ' I"-'1' 1I"lw' '' '1I \ . aft(l \ '•• h \ lIIaIl 11ll·<.':.lII • o f .l It,""f d",lf;IIK'I' ,C/. :: ~.-I l A id . f iIM!h . for ~" II I " lIlid n \ . i\ 111111'11 b~"r Ih.1Il , 1....·.11 1...• IIH",I IIf l ilt' ;.llIIillhh' r lllmc i\ , ·li·lIIilult..II ..·f.. re- t1i\tril lllliull ' ''lllilihnllllt i\ .11t.1; 1I'''''1. III " 11'h rs r 1·1I11I\1.llle'l· ' lill ... lil\~ \ '.. i\ \\ ,.rt ll" 1,i1,· if. Ior allY n ·'l...m. , li\p'",iti'l1I kir ...til "" we-rt- .lllo-fl ..1 .1/111III... wi\I 1 11I ;I\\ it:tl lilt' dl.lIl~' ·I " ah ,"n .. 1, Ii\t ri llllholl ur ,·lill1ill.lliulI. ..r In I.. "h .-\ lIul lll.'r \ i l'\\ o f di \lrihutioll ;II \ h'at l\ \ 1;11t· i\ 10 ('1 IT I\ icJ" r IIIl' roll in of ;l1 l1l l1 l11 t ill 1.. ..1\ 1.-\.,1 1" am",,"t ill II,, · illit;.,1 tl illll i..ll \ .. luu... (.- \.,1)' 111t' roth.. i\ " " (\ '1' Fn r .l\ pirilt .11 111 "' lli (~ Iii ' 'M·ill. llli \ ral it. i\ "PIII,.,illlalt ·l~ ~ , illtli,:.. ting th"l 11 · ,ln ll......m · ' ''lu.ll1~ ,1;\lri l' IIIt..1 hl'lwl,,'1I 11..· iu ili.ll ,1,llIli nll \ 0 111111" ;1Ilt! tilt' n-a IIf Ih.· I I~ . Fur ~.· 1I 1 .1I 11 id li II... r.llin i\I , i ll t!i l ~tl i llg th.ll .11 \11';111, \ t.. llt · 1II1Il'I. lI111n' o f Ih i\ 'llllil. i" h l' rI'\id", ollhill, ·. 11..111 ill\idt·. l ilt' initi'll ,hhilit'li \I,I 'II11t·" Fi ll"Il ~ . ;I UlIIlI''''''li,," 110'1.. 1\ tn 1M' III.ill, ' 1" '1'\\ 1'1'11 \ ',. and tilt' \ u llllllt' "f dl \l nllllllulI " ",..I In ''II!1\i ll.. r III" il1111lt'IlU ' u f p l.. L\lrl;l "lIt lli\\Il" hillcllll~ nil t1i \l rihlllioll . " .lo:.. , .... \ '/' + 1<:I." p . 111 ). 'l1wy ,m· I ·\'ot · Il I j;I II~ tI... .... Ullt'. ·11 ... 1t'T1!I \ '., ;lpp li,·.. lu a IlIt ..l,.] ill \\ !lil·h IltJ , ·lillli llalitlll'M't'II'" alJ(l,li \ lril 'll l iem 1"llli lihriult1 (..Il ·;lll~· , t ill ' ) l la\ I.. ·t·n
f.,r
"r'JII1Ur
·I\'"
nm. to Reach P1aleau
"'It'll
)(' 'l 'all th 'll fUf p m t'! il'a l 11" '1)0... ·\ pl.l""all h ...lid In 1)(' n 'adlt'l l lilt' ('1I1ll't 'n lf"lhlll i\ !Jllll " f C " . B' '''a ll\( ' of tli_lril'llli"" killl'li("'!<. lilt' lilllt' III n ·..d, p l..llt ·.m .lifT.·,.. l 'd w.·. ·11 p"" IlIi1 ;lIld li \\ II'· . E " 'n h in )'1' (" 11101. TI ll' h'nnil"'! h;llf· lif(· " f lilt' alllih~llt ·rt' ·Il ,i\I · age'lIl lIIl'ardipilll' h . l ppfll\ i llla l d~ 12 lIT. nlt'Tt'I<,n·. nlli ' \\'II" ld lI"nllall~ " \1" ..1 .) t lll uf II... p"'to-.i11 1'1.1\111.1 t1 >l1I .. ..nlr;lli"lllu I..· n ',ldl''III", I ~ I.r t illrill ~ a l'I lII..I"I1I'TiIh· illfu \ ;ull . III' k al1 illaLt'\ 0111 \ 1 Ilr ( FI~. IH- '; I. .-\ 1"" . ~JU'l •.r'lh,· plotlt·;U1 i\ n ·"dlc.. 1by appn l'(iIlMlt'l~ I.') lar iu ,lt'ac! o f lil;" 1·' I)/...1 I..l llI l. r (.1..1 . , 1 2 )' n li ~ t1iff,'n'l\('1' ;Iri ·\ 1.....~ l l l ....... llic.:;mlipillt' \ d l\I " "' lliulI Lillt'l K.....m " h ipl..l\i (·. \\1111 \111.· Irrill ~ t1l1nllt: till' fjf'>II" ..I-... •• \\ h id l I.~\ ;l ll;l[f· lif.· of .lpp n ,'illl.l,, · I~ \ la llli'll ,·lilllill.lliUIl ' ulI l~ ::!i l lm ll '11... r" "lIlt i\ ;a r.lpidl ~' ri\illC; IIl1ti"!I" IT\I' f..I","l.. ll ~ ;l 1IIll('" \ I'I\\I' r appn ~I('I I I" pl.l!t·.III.
".
CHAPlf P 10
20
B.~' "I 'I ,n"i rn"h·l~ 1 I..
. 'ill:' 19-7.
ln lu .. ~"'· h r . .....>l.ml ·. ..,, · i.v. tnfu-
.in" ,,( 1lH;'>lTl lipi ' ''' (11,5 I1IIo0.r1. II..• I"t..... a "''''.....n l ..II..'' 11;&\ rI..-" ,.. 5l"l'l lOr II..· p!..1to;
"''''1''1<' iI
1. -nllin..J
."" It'
0 4 II-Wl.l
Iwlf·lif., "f 12 I,.
'n
11,L. r.api<1"'PI' " ... t, pUh'"'' i, ll"Sull .. f o,\,..nh in pi....,,);!, h.oillK
"ri· pi,........ ..
fTWril) ' t'<"' I",IIo.. I I ~' an h, i1i;1] ....;Ih .. l...Jf·lir.. ,,( 211 ,,,In. ,I" rin" ",I 'K -" li",.. . iJ(Ili finltll ..
•• un'" r. "I< ", ;, ~
.. 1,,>1...
\.
h"""..ti""
,1<..... 11...
,L'l " ;,. re- II " ....." . of 3':' Iwlw-n" ,,;11, lII ilo l-I """Io-,..h· h~ I•..rh ·,,, i,,,, t I ml\"l. - :2.. 1 IlM). IK,.. I,,,,,,, (rum C•• • . K . C1ifl'.'. C;.<:.. Bio·rn ....... <:., \\ i ll;;. " ,•. R., S"I11I",j, S .. \1."· M"' """ . C;., c:....,..I)'. S.• 1.aI. C ,. \ I. , Q u.. n. C.. '\ II,I,,",, 'n. C ,R.• T II. l..· p;<~' .
2
o
r .. ;U"I W"l1 m, JI>. 111M1"'"
(·.... i "t"! ~'S.
24
48
\
72
Hours
r"arm.. ,<. I~·".."'i<'" >1,,,1
mini",,,,,, "fT...ii\,· dm io;...l , ~ ..... of InlnnM"" " Ilit·..nll l" ' .... e llll _ 11...,.. m;o(,". TI M·r ., -I;:711f>-71'l . 19'Jl1,)
111t' impo rtance of liot 11I11) ' tln- half·lin ·s but al..o Il.t' n·lal h l · ran-.. of , Ii..tri lmlio ll ilm l elimination Oil till' appmad l of th t' pt L"IlI;1 couceut mtion tn plate-au ea n Ill.' appn"l.·i(111I, all th t' d m~ is l'Ii llli ll al l "tlll ll rin~ lilt' h'nninal (and ollly ) phase I II this case. it takes I n-r miua l half.lift· (lI.fil.),'lIi'1:) and 3 .3 vuch half·lin "!; 10 rt ' oK·1i 50% ami 90% of tilt' plateau. rtOSpl"l.1 i\'l'Iy. Jl owt...x-r. at Im\'('r valut's of f l' mon- d m~ is l1 I m 's l)( Il l(li l\~I)" cltnnnatr-dlx-fon- di..trilmti on equilibruun i.. t· .. tahli..III..l. As a re-sult, til.· tinK' to ac hit'vl'. t· . ~. 5( )'l;f, IIf th t· plateau oc curs t'arlier until. when / 2 = 0; till' h llli ' n-quin-d
I1. ""
. ·i jt. 19-'1. " l'p r" ,Ol'" I" 1'1.. 1.·.." il) pt.,m... ,lllrill!!, a l, . " la" l·r..I.. l.v. i nfll~JI1 . Ii" a ,ln1ll: 11,..1 ,lhl,l ~,
Ilit"'p'". ·" "a1.I"p'.. ili,,n Id nt"ti<.~. n .1t" ,·nni n"I I~.Ih.. n ·I " .. r.atrs ,,( ,I,"' n l>( ,ll"'" ..".1 ,·l" " I"..h..... I" Ihi ~.on'
I,
100
0.01
"'1>1.0 .1","..,''''1'' " " 'IlIW .".·ffir......'h ).1..,,,,I
1..1" .,,"....." 1{....uh A. l •
Ill~ l.
;uKI tI,,· fr...·•
li" llal ..Ii"'i'....liu" k rill ..., .. Il;...h~ l ....ilh II..· h 'rn,ill;l! 1"......../2. i. ,-..lit..! fn,," 0.01 I.. 1. \\l...n ,IRlll: Iii' · llil",.,.. r.apit U~· (' ''lIi''' n~ 1 ....ilh .-!imin..Ii" 1I ifi "'.. ~ I I. II... It'n,,i,l;l! """f· li f" I" 'l n ~ . d..' Ii " ... I" pLat.....,,_\ \1 ..... I. ...,,"10M,. .. ,!t-. OJ}I . " "M1nl/;..liml".. f;l,\I" r Ih.u, <\". lril.'lio.... II ... "1'1:""......, I" I";I,I'~"" i. ,1t".. n "I'Ol~ 1
rn.... .... "'1'1""_'"
IJ
li"" .lOt, ·,," ",,'"' I'n", ..nl)· 1':1' ).1 ' 1 , ,,~,.It ..1 f,,, n.f'·.........-.· b; .1,,' ,·0·
1"'..1...11:'1.1,. f,,'1 ' II,,· "RlI: •."I,ihils''''' ''rnl...rt . " Ol'nl d 1..ri' lit'S if! .. I I. in .. -h it~, I 3I1'l;u"IIIl ~ u( II rLoI"'II' an- n ·;o(......1 ~' I ;1",,1 J .J I,·nn; , ....! '"
l """r·I1,
n "P'''1i\.. ~·. Xu,," 11...1 Ii"... i.
I in " "ih of I,·nni,...ll..,]f·!if.·.
20
o./----~-~--~-~ o 1 2 3 4 5 TimeJ(Half·Ufeof Terminal Phase)
CHAPT£i 19
321
is lilt' half-lift' o f lilt' firsl p!J;l"l.', f).59-VA I • 111C bod y OIlL'C a~ain acts lIS a si n~It-l'(J m part me n l , \ ' 1' For most dmgs/2 exceeds 0,8. and so till' It'rm illal half·lift' primarily ck-tenmm-s the time to reach plateau. Fo r uicanlipiue, sip lifican t eliuunation occurs lx-fon- distnbutton cqutltbrtum is achieved and hence the O!JSNvatiou ill Fi~. 19-7, Fo r ~t' lI l a lll i<:i ll . ,,;l h/2 dow to O. it is the half-life of the first ph 'l"l.', nsually 2 to -I hr. Ihal primarily detennim's the ti me fur th is alll i ll(~lyt:osidt' 10 reach pta!t'all ill plaxtna. Anlltl lt'r vie-w of events in plasma n-lates 10 rln- l'xpall{li ll ~ volume of di sl rih ut ioll 0 11 appro.\(·ll 10 d istribllliull equilibrium ( Fi~, 19-1 ), A plateau is reached when th e mil' S of infusioll and elimination an ' e-qua l. \\11('n distrthuttou iuto the lissut' is slow, tilt' (-ffl'l:tiw ' \Ullllllt' of dist rihu lioll n-malus fur SO lllt- ti lllt, dose 10 tl.t- iuitial di llltiull volume. \ ' 1' so Illal for a ~\"(, II mil' uf iuput tilt' plasma concentrat lcu rtws much faster th a n if di st ribu tion in to tissu t' is rapid , Tln-n-fo n - lLS mit' of elim inatm u = Cl.. · C, it follows that. for a ¢\'t.-II dt'antlll't' value, til(' appru.\(·ll to plateau occ urs earlier, till' slower the dis trjbut ion to tis-
but ,,; 111 a smaller volume of dist rihutkm.
sues . The phsmlt coucentratton al any ti Ul(' on app r oach 10 plateau e m ht' caleulan-d usiu~ prt'st'nlt'l l ill Fi~. 19-5. Hem r-mber for a dm~ with one-compartment ch aracte rtsncs lilt' conce-ntration at any tilllt' d ll ri ll ~ an infusion is WH'n hy
{'{lllt'( ' p is
Fo r a dm~ tha i exhilnts hit'x!,MJIl('lItial dlsposltion chaructert stlcs . II\(' corresponding {'(111
19
'" 20 Tln-se n-lations lnps follow hy ima¢ning Ihal to tal conceutranon is tilt' slim d{-ri\"t"{1 From h \1J h~l'Mltl lt't kal dmgs, t-ach \\; Ih the same clearance value. infllSl.'l 1 al rates I I . l~ , anti fl ' !l", n ·slx "(1i\"t,ly. E11llliliollS ls an d 20 em phas fze- tilt' impo rtance Of l 1. (and 11('11('(.' C I and C~ ) a.. well a-" Al and "~l in d('l en nilling 111(' t'\1.-n15 in plasma foll{J'\\; lI~ a constant-rate infu sion . Equunon 20 al.so permits ready calculation of the pe rcen t o f plat ea u reached at a uy tinu-. For exautple, if the half-liws associated with the first and tenntnal exponential te-rms an.' I ami 12 hr . n 'slx"(·tivd y, allt l / z = 0.5, tln-n at 5 hr , the co ncentration is 64 % of plateau. The converse, t.c. tilt' lillie n - quirt-d 10 reach a ce rtain 1)(-n'(.-1I1 of plateau. ('JlllIlul II(' calculun-d din"{11y. IX"(.'llllSl.' then.' a rt" two exponential te rm s (,()Il taillill ~ tilt' lin~1I( J\\l ' , time. Ti lt' tinu- cau II(' ck-n-rmtned by iteration (C hap. 1ft), i.e., hy sllhs tiluting dilTpn'nt lim ps into EII_20 uu til till' rigllt unswr-r is reach ed. In tlu- ecun pk- all(J\·t" th e time taken to n-ach .')( )f}. of plateau is 2.7Sll r, En'n ls in Pt' ri phe ral T iss ue . As illust rated ill Fi~. 19--9 tilt' tilll(' 10 adlit'\"(- plateau in slowly ('('l ll i l ih ral i n~ tissues is p rimari ly dete rmined by th e terminal half-lffe. irrespect ive o f tilt' lime rcqum-d 10 ll(·hit'\ ·(, platea u in plas ma. To app reciate this point, co nside r c....'Cuts in terms of tlu- two-compartrueut model de picted ill Fig. 19-3. \ \ 11('11 distribution occurs rapidly, dmg ill tissm' for IIIml of tln- tune is \; rtua lly at N luilib riUIll ,,;tll d m~ in p lasma . T lml is.
CHAP1U 19
k2 1~ .. k12A 1
Rate of drug
Rate 01drug
lea ving liuue
enlering lissue
21
and the rcfon-
22
which slll,"'S that the amount in tissue par allels tllilt in p!;l"Ill11, \\1I('n. !JIIW t'\'N , dist rihu tion is slow relati ve to clhntnatlcu. li lt" concent ration in pla..ma appmacla-s its plate-an !)t'fore much d mg has cnt ered tln- sl(," 'ly l'(llI il i b l'd li n~ tis sue. 111t' situation is the-n aual o. ~nus 10 a consta nt- ran- input into 11(1)lIIpa rtllle llt From which loss IX'(1 11'S. Accumulation is dctcrmtncd by the elimination half-life , whk h in thts case is a"slxiatl'(l with k:Z1, tile exit rate cou staut fmmlhe slowl)' t'f l ll ilih rJ,ti ll~ tissue . In real ity, the situation is s()lIlt"what mo re co mplex 1>t'(',IIIS(" of tilt" n,\"('rliihlt" 1II(J\"("IIWllt o f t°tv,"('("n pI.lstun aml tissue. :\011(>theles s. under tilt'S(" ctrc't nnstano-s. the con stant for tran sfi-r oul of the slowly l'fi ll il i lmll i n~ lisslll' is a major dlolt'nnillanl of the n-rl1linal mil"coustun t, "-1'
Bolus Plus lnf.sion Lidlx-aille is IIM'lIlo control ventricular a rrh)1Inllia.. in t'lIIergelley S('lt inl{s. A b olus is J'in' lI 10 rapidly achieve an effecuve concentratkm and is foll(,"·t'(l bv a constant-ran- infus ion to lII11int aill' ti ll' couce ntranon. Althnugh rhe infu sion l'\ 'l'Jllllally' ill'hil,\"('S ti ll' 1a...1 object ive . tnutally it ca nnot match the f all in pla.smil concentration assodun -d with d isl rih ut ion into tlu- tis.sue s. porennally I('ildi ll~ to a period of il1(,lTl"<:ti"lo couceutr aticus. TIll' r-wn ts an ' ,1,"pk'll'(l schematical ly in FiF;. 19-10. A large r ho lliS dnsl' u u tlld overcome till' problem but wuuhl IUSO inl'rl'll.,*' lilt, likeli!l,xxl uf Io.'
Fi ll:, 19-9. slw...... ;U'f' t· .....'h in pLo..tllll llIKI 5"""'~' t" llIilihr~li llll: li5' 5U.. fo,.. l"oo~) dn ,JC1 161 IKlt h t.Ii~' hit-':po:Mlt''' tW (1i~pti:lllonlll! tLo..lll.J li"rs 1~,rn"P' II O.5O'Illllll 1l()Il of tho· plal"'"1 pll
' 00 90 Plasma I, = 0.9
-- - - -Tissue
1 2 3 4 Timel(HalHife of Terminal Phase)
'29
0I5TI11BUTION KUTlC5
CHAPTl ll 19
illrusioll is to match tilt' 1It't rate or movement into tissue . T his rate is hight·sl initially. when
110 l!m~ is in tissue. However. a." th e tissue conce nt ration rises towan] plateau . the net 1I\00'('IIlPllt into tiSSIIl' pn ~n'ssi\'dy declines .
AN EXTRAVASCULAR 0051 SIOW N th an . list ributio n. so a pp roximatmg tilt' lxl
Oftl' n , ubsorpttou is
~
10
c
8
t' !t. 19-10. Altho:lURIl il l.lIus (\ '1' CJ ) ( , I. · Riwn 10 inilially "..hit" , · II ,,";,,,,!, pt."'''ll lielo..a; (UK.....•
§. 0
"
6
'"c
4
~
c
.i3 ~
hI tiM'
.~.
..
A
'
.'
'' '' If'lt'f)b ,
"",i,,~
10 .li.lrih" lioo Id_
f1l(' ol_....ed pi "
(u"" " lntlio" lIh 1.... ' • •1". (u >l<......1"..lid Ii....) (f.tt, 2) lUltl tlwt ,.;..t ed "1111 tI... ( 'OIut"" I· I1lt.. i" f".ioll {u >!." n '" dou.,lli".. ) ( ~:'-I ' 20 ). A 1 I.... UII M'("OI"'W'T "1I1~ do... ('>lIl . . . 1Q'o1'" 10 p 1.....t1o", f,Ulin~ ..·Iow 4 l" Wl.. I"ll tI ,"" Iholt hi~ lui-
B
0
e :::;
do
Iwli.:s . ~,ott' 111..1 (- - . A) l< I""
0
~
""W'l.. CJ. (..n~IIl" 1 i"fu ...." " I " n o. 1 10 maiolain It:.is .,.] .... (1'>11. , • CL , Col) fails lu
Inll ioll of 4
~ y
rat.·
' lui
....
,"mof IIwt
i.Ill
tial pL...m..(Ufl(Tnl ..... tit"", ( - - . B ) ""'~' ilK..,......... tiM'
2
.illlI..... "i lnxit:ity ll mWl, · 4.3 J.t M),
E
~
i1.
0 100
0
200 Minutes
300
400
HK. 19-1 1.
10
A,"
""."iatitlll-l
,I ~", I
0.3
\
I--...e
,
..... ----------....-""'1---..
+--~--~-~---< f----,
o
n.' lit1....is ll ... mi k~ lllInieplot of
1.....lieMl of , IIl:1rri o f,lIl"Wio~ 0 ..5 IO~ ...Imi"i"..·....!. " .11)' (tv.....O , 2.5·m~ lahlt..s. e )l" nItTn , llor. :. " "h...rpl ie,n is m OMii fioUl..,. Ih .." ,li' lrih., Ii<"" .. hipl ie ('''1''1-'' i, ctill .. , -n alt..,. ..U;oinnlt'T'1 or t"" I''' 'a!< u nlCO·nl r.. lie lll f"l1,,,,,·· ; n~ t ""tlnol ,lo- .... l l mlifl , · 1.3 ,, \I).(Tak.... fn"" H " ffman. 1),11 . ilntl !u-llrll " ff, J.: Ahsurl' tiuo .. f ,mJJ:. jtiw" ~m n pn,.......diorn . JAMA. 2:l2.-u57_ 9fiO. 1972. C"''1~Tid'l 1972. An...ric>ln \1...11t,.] ." cIh.. TOf';oO
4
B Hours
12
24
CHAPl'Ei IQ
330
tilt' 1)('111.:. ('(JII('t'lItmtinll. In th is situa tioll tilt' 1)(';\1.:. conc entration ami till' !iIIit' of its 1I('(1lr rt'1ll1' rh-pe-nd 011 li lt' killl, ti t'S IIf hnth ah sorp tion and chstnhutnm and minunallv uu dimi · nation. n it'implira tion o f tln-se- PH 'n is In dm g t1wrJ.JlY;!Iltl m llll ihl rillg:dt'llt'ml" 011 wln-ther
tln- sill' of
.u-mm
n-stdcs in 01 mpitll ~' nr 11 slnwly ('fillililm ltiu g: tisSUl', D ign\ in dbtri huh-s
slow ly iut.. tlu- ln-urt. IIU' largd 1IT'K
MUlTIPLE DOliNG 011 t'wllis d urin!: muhiple- tlllSilljl is illustraktl hy tilt' dala ill Fi ~. IH- 12. " I,t ai l"'l l fol lU\\ill~ a ll S-lullIrl,. i.m . n "';lJlt'1I of ~t' " l am id ll admi n is!t'n'( l
T he illll);lt"! o f t1islrihlllioll kun-tics
~
10
§. is 5 ~
•
E
g
8 c
:Q
\
1
" 0.1
•
o
2
"'-..
r 11 Gentamicin Doses. 80 ma
~
!X
'~entamicin in Rapidly
11 11 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 r
~
'"E
3 9-
10
EQuilibrating Pool
0.5
E
100 ,. 3 50 g
2
4
6
8
Days
10
-._ .
- --.---
12
14
5
~
"n3
3·
"3 o
16
n".
19-1:!. 1),1',,1,, 1 An ' "'mil"~:ari ll, mK' plu", "f ,I..· ·1. "f 1:",,'a"'K'" ill II..· I...." ,..",nTi,,!: ,Iurin" " ,..I Afk. LIll . "' hnini.t.al....' . 'ol) til\,(. ,J",..., ..... · I~i .. I.. I I "' 1".1"...".1I,:!' am""".) ' 0 a 1';,h' ·" 1 rur i'''' '''''r '' ,Lo~,, _ 11,,· hil' k ,I...~ " ... in .. ·..."n """,('T,'r"l ~", , • .1 " I..'T' .. 1"'ini. I.-" '....' "-a' 'h~'1 ... 1" .... fi ll,..I I" " ".. ""·1 11",, ..." " " ,10", l:" "'a",it~ " . 1i,'nl..," ·. I...." . .....' ;a.I. ", I~· ' '' Iuilihral inl!. " ""part" ..·" , a,,,I .. r"[>i1 duri"l: tI...,1!. ",1"'In · i. lrall. ", . "ill, hlt" · ,h..1,,.I''1I: 1o:" "I"lUit~ " , 1 ), ," ,,~ ", Imml-I.-..I" " '. ,I..· n n"" " luh,," ill pL...,,.. aflo" ,I..· :'Ii ll, 11 I..· ...lo..,L" . 1 f"",, tI..· f"rm " l..
Ii,,,·.
..·
",w " ......r;.. t . f i. tl..· h" ..· .i "..· 11... la.' ,....... a...1 \ ., i. II..· inili,J ,bl" lit" , " I..·...· " " I, II..· It ..." '''', ........ • , " """"',11,i. ' . I" odit.., ...", I,,· 1"·ri 1u\in" II,,· m"lhp!<·.. I<...i""'. I".,Ii<",' _\ I, ,, ·t.. I'~ 1_1>1. .....,""'i nl/: lIld .."I;u ... ..,. .J...,'1"...., 1,10,· "",II,,·n,..I".,.I u l lp _322 ) ( I mli'."l. .. I." 11\1). (" ,lap" ..l 11'1 " " Sd....n'~ JJ , " IKI Ju. l ll. W-J-: H''T ,al I·..·...-at • ",..1',,,,1<' ' ''' u'L I;,II, " f « '''I''llI'''''' _e lill 11''' ''n", • .1 11" '1,, ;2.t:lf;.l ~l7tl. lilT;' 11,1'" ..1,1<....1 ,.,110 I",·n lll..it.., ,,( ( :y \1,
I ~ .J
Q-IAPTfR 1Q
to a patit'nl for the t rea t ment o f a serious inf('(.1ion for /) days . St't'll are large lIul'tllatiolls in concent ration n-'s uhi ng from thi s regimen ami a lon g terminal half·life o n stopping therapy, In 1'OlIImOIl ....i th o tlu-r a minuglyt:osides. genranuctn is polar, ami while it distnblilt'S ra prdly into the e llr.K.'t.'lIl1la r wate r space, approximate volu me o f 15 L. it enters cells \1'1)' slowly. Accordmgly, althou gh ~c n tam ici n has a long terminal half-life'. 87 IIr in thls path-nt, the majori t)' of a tlt)S{' i .. eliminated hy 8 hours. a..sociat ed with the .. -h e half.lift· o f the- first pll a'\{' in Ihl' pa lie nt, Indeed . as a reasonable approximatio n. tlte temunal p h,I-">(' can ht· igno n "(l with rt'Spt't1 to t"\'t'nts in plasma. a.. was (lt Jl1t~ pn"\i ously w hen considering gt'llta mici n dosing (C hap. 18, Co ncentration ~I on i toring) , The n-asonableeess of thi s app roximation is horne.' ou t by the obsen'-"'l! rapid establishment of a plateau ill plasma ami by the co ntinuance of large fluctuation s in ccncentnunon, a n-snlt expected for a tlnlR wit t. a half·life of .. hr wh en it is gi\1'n 1"\l'I)' S hr. Asso d atcd ....ith th is regimen. oo....'t"\'t'r, is a sm' but continual eccumulatkm of dru~ in the slo\'\ 'I), t"llllilihr.lIillg ti.\SIK'S. when- it takl'S apprtedrn ately 12 d ays (3.3 terminal half.lin.'S) 10 n"'eteh plateau. Howeve r, at plateau. at.. cu mulation i.. 50 exte n...bv that mon° gt"ntamici n exists in the se tissues than. 0 11 It\1.·rdge . in tltc rdpit.ll)· t"(l"ilib rdting pool. Furtbermore. Jntle flul1uatitm of dru~ occurs in tlK' sl(,"1) ' t'~lll il i brati n~ pool. because of slow distri bution, Accumulation . both ti me-course and exte nt then-of an' clearlydependent o n sitt"ofme-aStlrt"IIK'UI. For RI'Tlta mici n litt le aet.'l mulationoccurs in pla...rna, and a pla tea u is n'achtod ,;( IU I\ aIter initiatiu Ktbcrapy. In centrast . e xte nsive accumulatio n occurs in the slawly t'c"I"ilihrdting tissues . ..... he n · it takes 111m'" km~l'r toattain plat eau . In C hap. 7. ba....-d on con...idl'rlltion o fthl· minimu m lImuun t of dnJ~ after the first WlM! and at plateau {p, fi7 ). a pJUPOMod index o f ac.. cumulation wa s 1/( 1 - f.' - it), As a reasonable approximation . th is tndexcan also he l·IIlI)~'t..J he re u...ing the approp riate- exponenttal ('O("fficienl. For exa mple. in plasma (A.I = O.171 Ir- I; t 111 - .. h r) ....itl. t • 8 hr. the accumulatio n index for ~'n l arn icin is on l)' 1.35. wh(' rt'a-~ in th e slowly equrhhnatin gplXJl (~ = O.()()f) hr " I ). it is as IIII1C·1. as 16, Tlse e....ents 011 stoppi ll ~ ~('lI tamici n ad min i...tratlon an' predictabl e. 11K' plasma C'()f)('('lltretton falls rapidly fo r the fin.t 2 days . .....it h a half· life controlled by the fin.t pb asc. Evenreally, h(I\\'l"\'-'r, elimluatkm of dnl~ from plasma i.. rute-llnntcd b)' return from thl' sl(I\\'I)' l"(ltli l ibmtill~ !iSSUI-'S. Except for the hi ~h dt."Wt't. o f Iluetuanou. the 1"\"('1115 seen in plasma ....i lh ~l'lltamkin are thoSl' ('''l)('(.1('(1 foll(l\\i ng a constant-rate infll...Ion for lIU)' d m ~ \\i th a low \"alll(' o f (Fig, 19--9 ), Sigllific'llnt clink," imp lk'lltiolls ari se fro m the d istri lmtio ll killl'tics o f ~cnta mici u . !l.l ost 0!'Jtauisllls agai nst whkh gt' llta midn i... IISl--d. rt'side in tilt' r.tp idl)' t"tluilihr..ting t'xtnl<'t·llular sp
It.
.5 ... :-: :;. - "i."'-· ~~ ,"",1· :;.~;.:":: ..... = ;1 "
5" - '" ~,-. :.... = !!. -' O iL =. "'~ ~ w :;_ i:: 'f=- ..:l:: .~ "'_x l!l . ,. "'' " ~. .... ... . ::' " ,
- f ~~~ a 3~~;';-i.f~
;a ~
[ "' = '''':f ~ 3l. :.;' ~a ·~i 'iii~- S~ ':'" :-:: ¥i ~.: J:=- .:0' 3 " !:, . , ~ ", !' !" 2 l :' f. ~ "'-: ~' :; ~ i. . :-, +:;; i!.;r ,. . " ! " i:;;..:;:
AmounVConcenlration, L
:: ' ,;7
<:
~_ 5 ~-:- i- = ,:t'i til -" _ " ... _. ", ~ .. r:. - _ J:1.
o
~. ..;. t' ,1~ ~" "'_a ~_ ~" ';: :r~ "'; t~i "~ • i:! :::": '! " ii" :"' =- ='" '::''' _._J~ ;.,,_;:/,"n :: :' _ " <1; :::. .. ..: ~n-. " .>-", J ~.~/l1- .. 11. .... _ :l
~ ~::' ~ = :r ;- ,... : : I =x_ -" i ;"~" -!~"t.'='" ,, ~ ~ _ -. = ."" = ! :: ~ s, '; ;; ~ !:, t' =,~.=-.,., :- - t. ::: - ;;- i'" ;;I ;! '" " . :: =' e !1 .5 _ Ai .. !:Jl, ;l :: 7 ]0; ;: i:!.!:> :L.. ,.... :- :, .. ",, "[=I . .. _ ..... ::1. 2 = . - 5 '! if i ' - :'·:l - !: ,,: ':0- ::- -= 3 ::;' .5 ii.
~
o ,,
if '"
-.,
,
~
'"
o~
'"
...
'. '
,
~
,,
~
T
... i:!
..l. · · : : ....
~ ,,1!1ji.·! .. ~e;.::< · = ... ~ ;~ =< =.!! .! .. :~y;, ~~ e-iii !!~_ !!i! !L3 ~=·~ =~ r~ i~; ': s- ~J; ;. :; :: a ir a !!,e :,' = ,~ ~-:. ~ i'-i,.:; "' > it l ~ " ll"j!! ~:; r; = -", .. J :;' ~1.=_ _: if il"' ·~ ..'f" r:.= .::~ -5 l=S,, i - ~'5 §:~ J=r -~~ -~ '"':~ ! !~=: e,i~- '!?-s...';! :: ... .. '5 "" ! ~ ,, " II' '5 f !. . ;.;:roTEl S" =u ~2. = ~=, L::' = ~-'J4i- a ~ ~.i" ,:::. :.. _ ,,-:z ji
... "
!~::o i ; = ?l ;= ; ~ t ~
~ i r- t _~ I,= ! ~K ,
1'1 ...
a,:i!
..
-
$j-
~r ~
... ""'"
i"
=- ! i :l
~:: ,;fE'I-' = ! - ., =.:l. ~ . " ._ ="~ ::... :! =" _ =1 ~ '?
'"
,-
'-
'"
,,
,,
,, •• •
..".. ",:
" riJ!!~ :;t != ·<~r~i; ~ __ = ~,..:i~ ;r ~ _i rt" ~ri i
l5
,..,
'"
C
o
,<
'"
o~
~
"
",: _ .: "
'"
-e
'"
, ,, ,, ,, , , ,,
=.',:
C HAI'TU tc
OISr~
KNTlCS
state does nul apply th n m glKJllt a dos ing inlt-rval: th(" plasma concentratio n Huctuates around a steady-state value . cwating a co ncentration W"cKlit'nt ht"l\.1o~"n p la...ma ami tissllt"'. 1I0\.\'t'\"t'f, a-" Illustrated in r ig. 19-13. as long as the fluct uatio n in plasma concentn mon is smal l. tbe con d itio n is sufficiently dOS(· to till' t rue stead y state that V.. om still "'t· applit-d to es tuuate amount in till' hud~·. n ils cond ition exists when input into the IkIl;l,. is s1l:",', n-lanve to dispnsition ldne tscs . or when the dO!iin~ inte rval is short ("{'!atn't' to tilt· thllI' tn aeh it"'l.· d istrihu tion equilthrtum, A-.. cne moves a\-\~el~" from this condnson. ei tlK'r wu h list' of mo w rapid inp ut (t'l tn-lIl(" lwing an Lv. bolus) ur I,,· \-\idt'n in~ tlK- tlosin g Interval , tht· dt...i atio n fnllll til(' tnlt· stt"a<~' sta te increases so that \ '.. has less app lica tion. ITKL.'I.,(I, if tilt' dosing Interval is klllg t·nough so that di stri bution equilihrtnm is OM:hK",'tod. the n \ ' ht'C.u llJt'S the appropriatr \"o lurn(" te rm to list' bu t. c1earl)', only tluring the te rm inal pllll.....·. n it' problem is t~·ra h'l.l wh e n dist rihu tion equ shbnum is nol lIChit...«J wttl nn titf-· tlt:~ing late rval, a.s is tht· C"dM" with gl'n tamK'in (Fi g. 19-12). Then tlK'" reltin of amount in but!)" to plasma concennauon is conttnualk- chan~ng. and neither volune- te rm . \ ' o r \ .... is ' 1;'1)' lIst' ful. F n..-Illt·nt !).·. IKJ\-\"{'\'t'r. tlistrilm tion is sllfficit'n t ~- ra pid to a1krw olK"-(.'Ompartlllt·nt dispositio n l'harolll1 t'ri"tics to appl~' on multiple tlo!iing at stt"dd)" state . nM -n, \ ' am i \'.. an' al mos t t'1lna!. and roi tht"r can lit' used to gain a reasonable estimate of amount in tlH' bot!)" .
AtTII!D CUARANe! \ \ 1"-"n discwsi ll~ th t· use of gt"lltalllicin in patteuts \\.i th re nal ins uf'llcit-ncy (C hap. IS. p . 3(6), 11"-' te rm inal pha.w is igrs orcd in adju.stin~ tJos i n~ n -gin k-n5 to ac bit'\'t' th",ra pt'utk: concentratsons . nil' reasonableness of this approach is illustrated in Fi ~. 1 9-1 ~ . Dnly tilt' initial hal f· lift' ts aht'rt"ll alUolIF; patit'nts " i th varying t!t-gn"t'" o f renal in sllffici t"I1(:)'; tilt' terminal half-lift' is virtuallv uuaffec t ed. The observation mav lM' reltionali7....d in titf-· follllw. ing manner. \\1It'n renal fUlKt ioli is u nimpai red, gt'll tamicln in th e rdpitll~' t'1luilihmting pool is mostly t'!im ina h'(l hefolt' dist ribution equilthrium is either lICh it...«J aftt'r ;k lministrerion of a holm. d OSt' ( Fig. 19-1 5 ) o r re-es tablished on stopp ing ill.tml nistrdtioll aflt 'r chronic dos h l~ ( Fi ~. 19-1·1). Under th t'St' ci rcu m..ranee s elmnnation lila)' be viewed :L\
tl~.
10
19-1...
S.·lI1il"~lll1t hm ic
pauli of II
... n "n " " .......U"Ii..n ,,( K"'1"mldn tn
r
In~" ... in
II...
r pooIlt'Tlh...' 11>
.li ff nl ,101C'''''" flf ........l rmllot~ _ .... 1 II) .,..... atini d " OITlU>l? CL,... afT"r tt' '1 '1''OK It",tllrnkin ;MI· 111Ini..t ,.",j..n S Ol ..... 11"'1 rn>aI ru nctinn Impounlln.1 p "';. m..,..;I)' afT....ot' tI... h.oJr·lif.. or ll... Ant pha · lIlld ,I..· .101"1, or II 1o·t"1uw In t"'...... ntnlolkon h.·r'll? 11 1.."ol...,] pIu..... i... n- -I.....I (I "'WI. - 1.Ii",MI. {Kro.I....."tl rnll n Sd,,·nl..~ JJ.. IlL, kll. WJ . PLauT. \ I.E.• Cumhu. TJ. \'1U1l.... J W ,. ;md Ah ru l}"tl. E.: nn.... J""nhtrtk... of K" nlllmlnn in n"'n , J.-\\ I.-\. 2.J.'l',327 12'Y. 1m . ("""","~I 1~';"7. A.. ... r_ ic'>on \1 .~ UoU
• o 107
0.D1
o
2
4
6
8
•
10 12 14
Time Since last Dose (Days)
'"'-u..ciA
d
334
D1STfI1BUT1ON KN E1ll: S
CHAPTU lQ
(mill vnlu nn- \ \ \\;111 a ch-aruno-, CI.. B ell et' th e rat e constaut for dL't ;linc.· ill tilt' ( i lld l1t1i ll ~ p loLslll a ) approaches CU \ ',. wilh 11 l,(IITt'Spn lld iJl~ halflife.' IIf o .r~J.:l · \ ' ./CI•. Hcduct ton in d t'liralll't' is thr-n rt'flt'(1('(! by an almost p mportional incn-ase ill half· lift, of tht' first pilot"'-, In contrast . duri ll~ tlu- terminal ph a.\t,. loss o f d m g From plasmu (;U1d tilt" mpid ly t'( llIi l ihm l i ll~ poo l) is cont rolled hy return fmlll till' slowl)' l'f i ll i l i h mt i ll~ liSSllt'S and lIul hy its cleanmce from plasma. :\l'('onlill ~I)'. tilt' te rm inal halflife.' is IlI lt· hall ~I "l,1. 11 0"', ("" ''', \\ith a reduction in clearance. di slri h ul io ll {'(Illilihriu m lake..,; somewhat !oll/.tt'r to b.. ('st ablislll'd an d. IIt'l',lIIS(-' II's5 d m~ is c linunan-d Ity then, ti lt' roncenrrauon o f ~t' llta llliti ll in plas rua is h i ~l l(' r comp ared .... i th tl mt ill a patien t with unimpairt'(l n-ual funt't ioll (J··i~s . 19- 1.J and 19--15 ). U!ti mall 'ly. if renal fullt.1 ion is 5llffidt·n tly low , tln- h 'n uillal llil!f-Iifl' is M'usilin' 10 renal fUlldio n . T heu tilt' first pha.'>t" prillla ri l~' n ·lIt"t:b di ~l rillU liuu . a.~ ..hewn in Fi g. 19--15 . Tn ap pre-ciat.. tht" last point, t'lmsidt'r ad m in isiraliull o f a bolus do'\(' of dn'g 10 a p atient wi lll 110 rena l fu ndioll. Dmg ill plasmn wo u ld ..till tit -clim- init tallv ....-ith ;l Illllf·lif(· dt'!t·flllillt... 1 so ld ,,' bv distnbutton. Be twe-en this extremeaud unimpam... 1n :lla! flllld iu ll i... a I"lmgt' (l\l'f whid l tin' n-rm tnal h:uf-Iift' d l,mgt"S nonceahl)' ....i t" rena l Iuuct kru. For gt'nta mitin , C" ails for mos t d rugs. :-.;'ow, In ret urn 10 a point mittIt, p n '\ io llsly alMIIII \ ' and \'... As n-nal fUIlt1 io n diminishes. so dot'S lilt' value of \ ', Thi s is a result o f less dmg ht,jug d im illatt... l lx-fon - di sl ribu tinu t"llui lih rilllll is adlit' " ...1. III cont rast. lilt' va hre o f V.. rt'IIl1UIlS 1I Ild lall ~t"t1. " 'il h ~t' li fa lll it'i IJ , couceru exi sts for t'Xt'l'ssin' accumulatkm in tilt, slow ly t"till ili h r,llill ~ ttssucs duri n~ chronic dos i ll ~. particularly in pa tients \\ilh n-nul Insuffici e ncy . 1I0" 1.'\ l' r. p n l\i dt ... l rhat dusin~ m it' ha s IIt'('1I ,l(ljm lNllo t'llllljX'm alt· for d im illisht"tl renal function, tilt ' risk o f lo\ k ity in I,.Itit'Uh .... t th n-ual insuffi dt'lIt, · should !It' no W('a lt'r than in tllt N ' \\i l h Ullilllpi un... 1 n-nal fU lld ioll . This t'\JIId us inn is l,.lSl,'t1 011 consideranon o f events a t pl att'a u . Tilt" amount in thr- '0111\\,1)' (>t!1lilihmling Iis'O \It's at 'O tt·a d), slillt' is tilt' di fft' rt'lIt't' 1It,tv.'t't' n tlU' amollnl ill ti lt' I M N: I~' (\ '.. ' C .,) alltl Ihal in tht' mpid l)" ("tluilih nllinK pt N: ll (\'1 ' Tlml is, UC.,('1.lrrill ~
mpitlly ('fluililmitilll-: 1)('01
e..).
. " 11:' 19-1:5. St·m l "~l h lTlio.· [' IUb nf lb.· . illl" I;t"..l ,....·h,lt· in ,Ilt, " L' -'lI1;t (~M " " nt r;ttinu i .\ '. I• .t" , ..tit, .imil..r ,,, ~,·n l ;tll1 i · <'ill. fur .IotT.·.. ·nl ,t."W''OM of ....,u1 f' '''dieM! fr"llI n In IIM l'I- .. f Ilnm,..\. :'\O" t k o' llul .. ..".I r""tiie,,, "rin...rily :UT...i. th.· hllIr_lir.. or Iht1i"'1 1'1",-... ;tntl Ih.' ,t.'f'lh or . t..l"1i.... ill ('(MI,·.· " l r" li ,, " h.. f"ro· tl,,· t" r/nin,,! 1'1,,,... i. r.."d.... !. "nli l " '11,,1 fllndi" n i ·0' I..w . \ \1lt,,, rt, ...1 fUllt i ie," i. wry I ti M: inilLal
..r"'r
, t. "~; llt·
;0 .t.i n llllu,..1 rri n...ril~· I~' oli'tri h.,· tin... ;t1,, 11 1... i"'l';t ir m""1 is rt·lI...·,,·,I I,y' d,an~ .,. in lilt· " ' m ,;"..1hllIf·hft·.
Rena l Function (Percent of normal)
10
o
~
3
o
~ E
1l
:5 0.1
10
<.>
o
"
o
E0.01 ~
33 100
0.001
o
125
250 Hours
375
500
Ct-WTE9
rc
ClST918UT1ON KINETICS
~ffiO\If1 1 of drug in slowly equilibrating =
msoes at steady stole
IV _ V) u
.C
23
ss
I
From thls I.Lst n-lunon ship il is S("('II that , p rmi dt"ll dosi ll~ r ate is adj usted to maintain a sh '"dy-stalt' p l,Lsmil o uux-ntratiou. tilt" amount in Iht" sluwly t'(lllil ib rati ll~ IiSSUI'S is unaltered. a.sIXII II \ \ and \ '" an' pu rt,ly dislrilml ioll terms that, at Il'asl for ~t' l\t a m il'i Il , an ' IlIIalk n 'tl h~' n 'llal iIlSlIllidt'lIt·y .
~in·tl
Changes in (olKentration and HaK-rlfe A ('t md ll di ll~ (, mlllll'llt is m-cdedhen- about (:h an~,'S ill plasmu concent ration am i halflift'. cOllsidl' r tilt' follm\i ll~ tlln"(' questions. \\1Ial is tilt' Iillll' llt't"(lt"(l for tln- plasma t''OIIreutrutton III t ill by olll'-half followin~ all l.v. bolus do st,? How lon~ tlot's it take 10 reach .5()'k (If plate-au folllJ\\ing a constant rail:' in fusion? \\1ml is the dosillV; Intervalneede d to en sure th'll the- maxumnn ;U1d minimum pl,Lsmil concentratfous OIl plateau differ twofold foll()\\i n~ a lixl'lI-t1oSl.· nmltipk- Lv. bolus rt'¢lllt'n? \\11('11 dislxKitinl\ kineti cs is characteril.l'l! by a 11I1l'-t'J l1lpa rtllll'nl model. rlu- lUlSW(' ~ 10 all thre'e• question s ure simpl(' allli the sanlt': lilt' k limination) half-lift,. It should lit· appan'llt, however. From what I.'LS IX"l'11 dis('usst'd ill this chapter. thai tilt' an swers cannot be dirt't.'lly inft'rrt"ll from tilt' terminul llalf-lif(' \\"11t'1i d istrillllliflll kinetics is evi dent . 111 (On, termtnul h,Jf-lift" or illtlt"l"ll any halflift" ('l',L'it'S10 han> simplt, applil'lliioll. 11.1' lUlSW(' ~ 110 IOIII-":t'r lit, just in 11.1' half-lift' \'lilue of lUI t"IXlllt'lIlialll'nll hilt mlllt'r ill lllJ the p;lI'anlt'te~ thai dl' lilU' tilt' entin- phunuac okiuctk- mo del (t·.I-":., C ], j _I ' C 2, j -2)' KIl( )\\ill ~ these p;mUlll'lt'n , rlu- lillll' 10 adlit,V(, any couwut ratiou r-an lx' calculated dll rill~ and foll( )\\ill ~ d m~ admiuistrution .
STUDY PROBlEMS lAnswers to Study Prob lems ore in Appendix II .) I. I>dim' Ill(' fllllo\\il\~ tenus: inilial d ilution volume, \u llllll(, of distribution dtlrill~ INmina l ph,L\t' , and \'OIU lIlt, of dislrihut ioll at sleady state. 2. Comment UII lilt' f(JlI()\\i n~ statements. a , All d m ~s an' (', pt,t:It"l1 to t'xh ihil t1isl rihutioll kim-tics . h. Fur IIIOSt d m ~s it is r easonable to n 'pn'S(' 1l1 the d ispositi on kim-tics by a comp artmental model. wi th dim ination cccu rn ng ('xdllsin ·ly fm ill the ('(onlral COII\Il
'."'.19-2.TIME lmlnl
I
Pb!>tT'IQ hpl,," COOCe
98
2 82
o ~ ~ _ ," f ~ /vi ,..j ~~ X. ~71313-IJIQ 1%8
...,.,J"-"
'0>0 "'9/1 •
5
4
8
"
33
12 22
15 17
20 12
30
45
00
70
75
37
18
12
Pto-mcx:oIo .....-o <J
..
~ " ,.M
"I"MlIlt'utial equation that fi t these d ata (C l, j 'I ' C2• J' 2) and tlx' initial and tt' nnillullmlf-li\1.·s.
u. Prepare
CHAPTER 19
b. From tilt' (Xln Ulll'h ' f val ues ill MaM, c- aIclllal(' C L , V \ , and v, c . Frum tln- btexponeunal equation , predict the plasm a ccncentranous at 10, 50, and 7.5 mill a nN tilt' holli s dose.
19-3 .~ ~ CONC~N1R"o,IIONLmsflt
010 0 25 033
05 007
fAST""ClT'fL,t.IOIl
1.30 1.03 0 89 0 72
1.20 0 ,9 3 0.7 6 0 .54 0,41 0 ,31 0 ,19 0 .13 N O'
0 64 0 .59 0 _51 0 47 0 42 027 0.17 0 11
I
2 3 4
8 12
15 ~"*-~ """'doo:> ,,,""""""', ~'" M
:,
3 ....
'N 0 8ooIo:M dooo<"""'
N .D' NO.' N D.'
e-
~y , Sf .W,"if' £M p ~. op l'I-o>nocol Ihoo 40( 1)-.O lQ 1980
~"""""""'01' '''''''''''''''~01."""",,
"One "'QIl
SlOW ACHVl....IQl1
a...
~. ~M ondE'-"' , J
fllod
ol.......
a. Prepare S( ' mi lo~ari t h m i(' p ints of bot h set s o f dat a and. usi ll ~ ti lt' method o f residuals, den-rmuu- the va lues uf ti lt' paralllt'!(' rs of tilt' biexl)(lO('n tial equation s that fi t r-nch sd of da la: C .' ;' 1' C 2 , ami ~ , h. F Wl1I l hl' values in MaR, eol.k' ll:tll' C I.. V. ' and v. \\11ie h of tln-se- pamnwl ers show(s) majo r di fft' n 'l\l't'S between the s1nw and Iast act' tyla tof plwl1ol)pt.'s? c. Is Illl' assu m ption tlmt the live-r am i kidn (')'S an- part o f till' initi al d ilut ion volume f('it-'illllaille? d . Had data o nly bt'('n avetlable from I hr onward. so that ouly th e terminal phase is (,\; t!eu t, what values for \ ' ami Cl , would he e'ol.ll'u latL'tI? Compare th ese values for ti ll ' slow ami fa.'it ace tylators wi th IhoS(' ob tatued in part Mh .e. \\l mt Fract ion u f tilt' doS(' t'l iminatt'li is it-~S(X'i att'<1 with tilt' te n ntuul ('xl)(lllt'n tial term for ('a(' h sllhjt'<.'!? f. Is it n-as onahh- to ('(md ml(', for b oth subjects. thai th(' tt'rm ina l half·lif(' will prind pall)' den-nuhu- ti ll' t illlt' to reach pla teau in plas ma following 1I constan t-rate in fusion? 5 . In Fi~ , 2 1-9 ( ~ It'l aI M ll i te Kim-tics . p . ~ I ) rln- plimlla conccntr anons o f til(' la-n zodiil:l.t:pi n(' halol:l.l:·pmn an ' show n durtng um] follo\\;ng an oml dos,a ~l' nW "lt'1l o f -Hl mg o f lilt' dnlg ( '\'( '1')' H IIr for 1-1 d ays. a. \\lly is tilt' plasma roncent rutiou o f hlllll:l.l:'lliU Ii lI11('tllatillg mar kl'l1ly ( '\'( '11 al steedy sta tt'? h. C all li lt' terminal half-lifl' nf lIal:l:I.I:'l)<1I1I lx.' dl'l ('nni lll'(l d uring ad mini stmnon of til(' (h lSa~l ' flW llw n ?
:137
CI-W'TH' 10
6. A IIlUdt'rdtd y polar dm g is di milmletl t'lI lin 'I~' by n -u aI exert-non. FolltJ\\i ng a SH.. lIlg t.v. holm dose 10 a (i..")..J,;g he;alt hy su hjt'(:t . th e pl('I"( '(I 10 dl'l')iTw hi t'xp' lIlt' nlia ll~~ C (mWL) = 2.711' - " 11M + 1I .(~l4t, - u , ,,,,,,, . wln-n- t is ill !JOIlr... 1111' Iracnon of tilt· dn lg ill pLL~ lIIa unbound is 0.37 a nd is ind l'!"N'lIdt '1I1 of dm g UJIll"l'l1tmtio ll lJn'r Ilw " m gl' '>('(' 11 ill plasma. a . Gi \'e n thai l'Iimi llatioll 1I('(·Ilr.. onlv Irom ti ll' init i<11 di luti o n \l,lu llll' (o -nt ral U IIII' part nn-nt }, e.l.k ' llah· lhl' folltJ\\illg ·phann.u."l,kindk parame-ters : \ '1' C/. . (l... . lip ' tioual] . h. COllllllt' ut 1111 ti lt' IIIt'(:h ani slIIllf n-nal excn-tiou of IIIl' d m g und ti ll' a p pmpri a h'llt"ss of till' assump tion t ha i eliminati on occurs o uly [mm the- o -ntral compartment. (-. OpliOlI'II: {"l lllIIlWllt lin till' d iS('n'Il
v
plateau." 2. COIIIIllI'III U II wilY a p nmollll t't '(1 hit'xpom'lIlia l l' lrn ' is St'('n ill II...• tit-d im ' 1)f plasma conccnt r anou pustinfll\io n "fiN slt'ad y sta tl' h,l~ 11('('11 n ·lK·I]('(1. 3. \\'o lllt! ~UII (' xpt'l11 0 have dd t'(1t"t1 a bi" xPOllt'lIti al l' U\ l ' 0 11 slu pp ing lilt' infus io n
I .
at stt·ady stall' had lilt' di spo sition kluetrcs (If Illl' dnl g foll(l\\ill g a 5()"111 ~ ho lm tluSt" Ilt'1;'11 t1.,fillt '1;! by lilt' equation C(t ) = O,Sf'll' _ 0 11M + O. I.k - o ,nYll, l1 MI is, tjn- snnn- t··'lx lllt'lI lia l l"ll(·ffidt'llh, hut di fT(' n'llt t"l l("ffid t'lIts compan-d wit h lilt' i.v. II(IIIIS tloSt·, 111(> [ractions o f tlnag IHlnn'llly excre-ted IIl\d litn~t '(l aftN i.v. ad lllillbt rati tlll of hoth lilt' ur-uromuscnlur h1( ){'~i ll g
~E
60 40
~
s
a.
20
.;ij • E 10
~ , -
e•
I!.
\ '"
'tl . .... o.
'.
~-
':" -e
~~
500
7 S 3
"
... Q.
~....pa~u~oni~m
.. " .0
300 200
. .......
'\"~-.· ''' 0-.".0 " " · '<' · ,o
u-Jubocuranne - -_ .
.-•-e a li
~ 3g•
100 ~ ~ . 70
SO
30 0 30 60 90 120 150 180 210
n 0
~ ~
t' K. 19- 16. n ..· ' b'l .....'llUt' lind ...... "f t!·lul.. '.. ~'ran',.. 10. • 1 ",...1 p.o,...~ I,.. ..'inm (Q . ' Ii... I',at....'h ....illo 1 10 ..u nnal (t ..lo ll"'n ) and ion.. 1""",, 1n -r,al f" , "", (---). I ft I..-" fn.." \1,1· IN . 11.1>.: 1'I 1I ~"'i 1X.. ,,( """.-\0, " .6...."" ",..I t1"oir "",..l,."'" 1.. 1'h.om ~.l.",,1M ... of ., ,,• ,,,,,I,,...i.&. t:':l lt.,II ~ C 1'":"·.H"I h a'KI C (:. IIIll( ( h.fn..d . ftI.. 1\...11 St... ... ""'· I'lIhli<-.llic"'. I.i,," h..1. 1!J"r4. r . 2.').,.)
..
S is ,
Minutes
8. In T ab le 1~ a fe lish'() ti lt' tlisp(lsil io Tl kim'tk pman wlt·!'"S of Ihl"l,(' ix . Olllt'si hel il' t l m~s , a lft' nt llllil, (t'llt an y!. a nd suf..nl anil. ~ (Jli{'l.' t'ad l n" plin"(l th t' SIIIIl tlf 11m ...' t·>;ptllll·ntial Ipnns to at!,"« (..al l'l)" d l'S(·rillt· tilt' killt'til"'!i aflt 'r si nJ.::lt, ix , IMIIIl.\ dost"S.
, D
,...... DllapeSltI_ ..I ..... •
~_.eten
AlffNT.......
c;.
c;
~min - IJ
.i. J]m,n -
'J
Te<m,nal hoJf.jife [mm]
I",-w...... Aae.tItetI.
HNTANVl
0830 103 0.120 0 _052 0050 0 ,0062
.i. d m,n · ' I
..".,..
CHAPTU IQ
084
0.080 0.037 00015
015 0030 0010 00012
461
577
0 _b7
0020
III
5IJ'ENTANI,
090
0"
Om" of rlu- critical factors in tlu- liS(' of lilt"S(· d m w; is tilt" tum- taken for tilt' plasma couccutratiou to fall O TI s lopp i n~ aduuuistra tton. Gt'Ilt"r-.J ly. the sho rtt'r tilt" tune, the q uicker the p;ltit'llt n -covvrs. a desimhlt' chamct eri stic. TIlt' t'(llIations la-low descrtb- tht" plasmn (Ulll,"" tra!ioll ut rln- t'mlof an infusion of dunation r. C(t ). and tilt' fraction of that concentration at tilllt' t,~", aftt>r st(JJlp i ll~ Ill(' infusion.
Froction of q r) Ol 'pc»I
""
['1 (1 - ,, - )." ) " - ).,,,- + ,2(1 - 6 - ).1') ,, - ).1'-' + ' 311
-
,,- l..J') ,,- l..J'-'j/ q r)
wln-n-
C;.C~ ami C; a rt" de lhll'(! in footllott' II of Table 19.5. These equatlons a rt' expansions of thost" Wn"U in the I~('nd to Fi ~. I ~. whidl app l~' wlu-n tilt" di.spositioll killt'tit.'!i art" dt"st:rilN,'(I II)' a hit'JI[X'IIt'lltial equation. a. Cak'ilutt' the values of f .,Il' ami hem, ' / 1 for alft'ntallil, ft 'lll illl~'1 alit! sufennuul. h. Cak'ulatt' lil{, fr.lt.1ioll of 11.1' fili al t.'lIIl,"ulnttion for t"ad l t1 m ~ ill II." follo\\ill~ Iililt'S afh-r stopp i ll~ an infusion of l -lrr duration (t = nOmill). Alf{'ntanil t,~ = 24.5 min Ft"nlanyl t,~ = 15.6 min t,~ = 14.8 mill Suft'ulanil c. Gi\'t'll that tlw palit'nt a\\".lk('IlS wlu-u the pla.sma (llll{" lllmliou falls by 5( )ll llflt'r stupping the l -hr infusion , II)' refe rence to ~ullr iUl!>'\\l 'r to -h-. {~ lI ll llwn l un tilt' Il lil il~' uf Ilw It'rminal half-life (Tahlt· 19--4) ill pn."{l il1in~ durunon of action of the th ree is . am-stln-tic drugs.
33.
d. \\'ould tlu- mllkill~ l)t<;my di fTt' n~lll if tilt' ph slll;l {'1J1l{'("nlmlio ll had 10 fall hy .')()il a fh-r sl oppi ll ~ all ill fm io ll at sl('ad y st all - le-fon- Iht' patit'lIl ;lwakt' m ? O l in l: I II amiWt'rilll!: thi s ' llIt'st illll ~nu IM'I'(l lu dd t·rm ilu'. by itt-ratio" . rln- \111U(· (If ,,..... ill (',tdl of lilt' abon· ('(Illatio ns thai W\l... a fraction o f Ilw slt·ad~'.s l ;lh" ronce-n t runon of us). e. COll\lllt'1I1 011 tln- impild of the- duration of infusion \\'111'11 ;\11I'lIIpli lll: to rom" tilt' durano n of ar t ion of t hl'~' three t1mW' O il st(Jppi ll~ itl.lmi nistm linll. 9 . 111l' d islxl"iilioll ktnoncs of \;,lil' lie add fnll(I\\; II~ a .'500-1111: hol ns ,10'01." is t'!la r.K"kri /.l't! by ,Itt' ('(Iuatitlll C(IIIW!.) =< 37,·-0 ••• + 57 ,, - ° '''17' , wln-n- t is il l mill. a. U si ll~ tilt" appr opr iate ('(Illalioll in Tllbl(' 19-1 . caknlate th t' \ '.. for this d m~. b.
11w dal'l can also ht · dt ·s(:riht ...1hy
k12• k:u . and k.,,. ( I l int: USt.· the t'tllli\"0l1l' 1l1 relatio m hip fo r C j 10 t':11(1Ibh' .1;2" ami Ihat for 1.., ~ 10 caknla tr- k,o') c. Coufi nn tlMI Iht· \";lllIt· of \ •••• calculan... 1fn lln \ ', ami tilt' lIlit'm 'ot-'(lpit' r an- t,(lm ta llls. a~n't"!i
with
~'(lll r
R
answa-r lu - a. d. U l i li /j n~ tilt' appmpri:III' values for tilt' m it'n lSl'('pie rdlt· eoustuuts, (-:11<11Ia ll' Iht" r ll.pt'(1t"(I Il
PHARMACOLOGIC RESPONSE OBJlCTIVES The reader will be able 10: 1. Describe. wirh el(()mples, the telatiomhipgenerally expected between a graded 'e~S6 and ccoceoectco or the site of action. 2 . Show graphically how one con readily deect when response is deIoyed co-cored to plasma drug concenlfolion alief a single dose. and give alleosl I'WO expianoTtOnS for the delay 3. Descnbe !he parameters 01 the model rhol ofren cbcrcoedze the relol~ip between response and pIosmo concentrOlion ,
why durotion of respcese is oken Pfoporfional to !he Iogo'irhm 01 on Intravenously administered dose, and when il 1$, calculate both !he minimum eHecllve ccee and The
.d, Exploin
eHective half-life. 5 . Describe the inAuence 01 distribution kinetics on the relatiOnship beweeo durotlOn 01
IE!"
sooese and Iogollrhm 01 the dose loIbwing single i.v . bckees. 6. Show glophiColly howdurolJoo and inleMity or resporu.echonge on leper"".-edosing when each dose is given [ust os the response and concentration 101110 pedesemired levels for drugs showing o-e- or IWO-Comportmenl diSlributoon dlOlocteriSlics. 7 . snow why response 01 fElVefSibly ading dlugs declines linearly With rime when response is ptoportiooollO the Ioganthm of the cceceoecnce andcooceonoeco declines 8}:;pooenloolly
Til t, h;l-~k p rtuci ples SIl IT{)lII ll l i ll~ the l'stablisllllJ('1l1 o f an up prnpriate d OS:IW' rt-'~mt'lJ an p resented in Cha p. 5. TI ll'S(' principles rt-osI IW
CONCENTRATION AND RESPONSE Bt't'llll."l' sltes of ac t km lit, mostlv ollisitll' tilt' vasculature, tlda\"li Ont'll t'"ist ht'lwt '{'n plat't'nu-nt of tlmg inlo b!tltltl a m) n~I){lnM' p roduo -d. Sill'll tlda)~ can uhst;lIn ' 1I1l(It'rl)ill~ relanouships Iwh vt'{'n l'Ullt'('lltmtlnn a nd n "I){UlSt', Ollt'!){ llt'ntial sol11tinn is 10 IIIt'lL\ lIn ' cnucentranou at the site uf action. A lthlJll ~h this lIlay he possible ill an isolated urgilll system. il is ran-lya practical solutinll in lnnnaus. Apart fm lll ('Ihil'll! a nt l lt,d lllil'lli issu es Ihal ariSt',
341
many
rt' SPOI\Sl."S
ohst, l'\"("(! i/l l'iw repre sent an integration of
muhipk- effects at
numerous
silt's. Another approach is to develo p a model that inl'O'l)omlt's the time -cou rse of dru g mownn-ut I W.' t W I "t' 1i plasma and sitl" of action , the reby predrcttn g "e ffect o r site" couceu lrations thut can then I)C.· n ·1;III'(1 10 respo nse. Yet a nother approach is to relate plasma concent ranon 10 n.'S p O Il'i(' unde-r steady-slatl' co nditions , which uhviates conslderanon of distribution kim-tics . \ \1mh'\l'r the approach adopted , the resulting conce ntration- response rt·!
General Equation A ~l' Ilt' ml cqu.uion to d" SI,.'rillt' lilt' t)pt'S o f observations see n ill Fi!!:-". 5-1 and 20-1 is
Intensity of EHe<:! -
E . C' ECfo" + 0
wln-n- 1:".... and EC">l' art' as defined a bov e anti 1 is Ihe ~'llo1J(' fonor that accommodates the shapt' of thl' curve. Till' illh-llsily of T('SPOIISt' is us ually a dJaIl!!:l' in a measurement fro m its basal value expressed a.s dlher an absolute d iffe rence , o r a JX'rt:e nl cha nge. Examples an' an Incr ease in blood pn.'ssun' ami a de-crease in pen.'t' nl o f ne uromuscul ar blockade. Altll(Ju~h e m pirical. Eq. 1 has found wide e pplicatiou. Certainly, il has th e right pmperties. Fi ~ . 20-2:\ shows Ille influe nce of 1 011 th e sha pe of the ccucentratlon-respouse n-lutionslup. TIle la~t'r tilt' vahu- of 1 , the greater is lilt' change in res ponSt' with concen-
Ch ..n!:.., in rhe electroence phelolian frn l'........-y ........ foll, { to ' I"",ntify 1110' "' Iho-tic t"ff....1 of R( - ). k "''''i..... >l'MI s ( + )· Lt"la mint" in a . " hjt"O:f who r("('t" i\·t"r1 ",n inf kMl of !10M(' No.., ''I''JooU ioorTW'n on ~..I.. . ·IK. 20- 1.
S(+ )-Ketamine
!(nf>hil'
Ec", c c
I
50
n ~ ~ ~
a:
""
25
,-
R(- [-Ketamine f
0
•
E_
~
~
c,
1 2 3 4 Plasma Concentration (mgIL)
5
"tI is !Ill' I"f"n~'nt n"(!,x1io n in I..... " Ii.." f"""'l, ..• ~ pLum.. <~ .... '·llll'llh" n . Ahl,o"gh <'hu;u;1..rhl ic s .•h"'Il,..J, or .igmo.d",I, <'U I'"I, " lU"E' """'n with hnlh UM'nI""'IKU. tt...,· ,liff..r ill Idol'. maximum l."fT."(1 . tlio>\,-d. #-:_ . ;mtl ('OIl <..-nlrati<.n '<"(Io.-d 10 l'T'udu,'t" 5O'l ..f E._ , Ih.· #-:C..... Tho L.li
Ol"(."' i<Ml'. s lM
\'l."~ 1lPi.'i. !'P. 196-210 .)
34' tration anmnd the EC,.,., \<4111(', Fo r example. if., "" I then. hy appmpriah' suhstitution into F'
f)( )'l,
of lIl;t\ illl a! n·spollSl.' art" 0.25
alltl -I tunes fX:....... n~I )(·l:tiwl)", a 16-fol
m lllt'llf y is close to I (F ig:. 20-3 ).
A
( ~·II{' ml1y. lht.
B
Shape Factor 5
100
tilt"an 'ragc'
val u(' of y lit,S bdWt't'1l I andS. Occe -
Shape Factor 5
100
2 ~ ~
c 0
~ ~ ~
or
~
~
1
s 80
0.5
or
~
80
~
II
60
.. 60
•:; 40
••E
~
~
:; 40
"'~" 20
0
''"" 20 ~
~
~
e,
o '"":::::....-""'--~---~
0 0
1
234
0.1
5
10
1
Concentral iOnlE~
COncenlrationlfc...a
,"" h.
tlR:. 20-2. 1,;" • •.., (Al '''MI " ·",ilc ~th ,,, i<.o (Ill .." ... ·" tTodio >l ,· n"'j. "'''' Im ..IiI1,..I ..,"nliul.! In E'I I. fur tI'n.... 1,~ldh.i i<..,J .IAI!/;' t11;11 II;I'l' II......." 1£ 51' .l,1 dilT"n'nl .ti..... y. .\t Inw " IIl' ...·ulratit ",. tI..•..1T.'<.1 n ·..._ ..J1I",,1 1i,,,· I~· "il}, c.." ·" 1..."'.'" (:\). wlo,'" y _ I, "I'I,n••d'illl.! a ma\i mal .:aI,,,, ..I I,ij" " "In'"lr"' it"". n..· !t"••" ." th..· .·",Io",· ..f y. tI,.. .h ..·pt'.. i. li lt, d l.U1W in ......, . "'.... .n"""I II",· IX:,., "..II",·, floriv, , 2f1 aJltl ¥l'l " f " ...,h"al ..fTt"(; (.....1,,1",.1 ,L.,I"..I Ii,,,,., l, ,I... nosl"""" . 1'1"'''''' In I. · 1'"," 'l1itll",ll I> tl,,· It'lo!arilh,n nf tI... (l "... ·" I... (81 fi,,, all •..J,It.. nf y. ( ;.>IIt. '''lr.ll it..'. ....' ....1... .... ...1..d ali'" I.. f:C" .
i,,'..
"'i""
nit. 20-.1. 11."'1" "'.... n..• " n..ll -.;. tilt' pt'.",-nl .It......•...... i" ·n i h" I" t1 I;Ot~'~~"I I" Im lr""'ItJol iflt-'ft ""'" i ll, ,I",.. ""1"",,,,1 , '1'1....· tit", " f lilt, ,IAlt.: in I.r....",a, n ".. ,L..", r" ln" Tt' lfMoI",,1 lilt· ..." " " .." " "fl,'" .i"J,:It.. ,,' ItI 1ll"lt,plt.. (,laily) or..! .It of !\O.. ~tIll1: 1",lol.i . "f Prv1' ....u"'... 01 I.e) 'Il" '" Ifill-mit .".I.,j,It..I-•..!.......' ' •..q>•,,1.. (0) in an i....li..it.lu,1! 'lI h,.'<.1. n".. C'l"'m..lli,... i. tI.., lil nf ~:CI ' 1 h . ,l it.. J.o,,, . n ".. "..,.."'.... ;tIlpt'an 10 folk_ tI.... f;_ " ....Io..J ...; Ih;t y ,,( I.. an
40
8
• ~
.
•
•
f:_ of 4ll'l- , ......I ;t" f;C.,., <Jl 5.31<~1~ (1I.... lr"",, f".." 1.;olc1t.. 1t·. Rl_.. sl ,b. It.J., r, J.A., Botto.ff. \ l.B... ""Id \ Ii ; •. 1),\1.: 1'" '1 ,....,It.lcoi
Pit,..·
I;.,..."'I<· lI u lt ..1i"lt ".inlt ""I....I1ItI ...,d ' ''I ..l ' ''''', ntr ..lio". in "....lthy ....lun lt,,"r,. J. 11"'"1laII....ldIMi . Rit'l.lllann., 15 :9'olh~'l2.. 1 ~'l7 .l
,,1o,....n;
o
~_~~_~_~
o
5
10
15
_ _
20
Unbound Concentration, 1Jg/l
25
C ~PfH
20
siollally, it is much Wl'a tl·r. ill wh ich l'a'\(' till" d Tt'l,t appt'a~ ahnos t as an all-nr-noue respo nsc. lx-cause the r.Ul~t' (If coucent rutions lL"....)(1ah '(! with min imal am i maximal reSP O II<;(>S lx-corm-s .... 1 narrow. Patients di fTer \\i dl' ly in their values of f:C.,," 11lld y fnr II gin 'n dm ~. Part of th(' \.uiahi lity in f;C50 may hI.' diu- In difTt'n'II{'-'s in ptL"1II11 protein h ill(!i n~ , a" ft'Spo nst.' depends on unbound
i,.
40
Fl!\:. 2~ . TI... n",,""'''' ,Lit.. in Fil:. 2lh 1 ..... "-pIt,n...1 ,.\ lh.· '''J',,"thm of Ih .. ""h..u 11,100, t"..
~
., ,, .., ·,,t rollifN ' _ a ."m""", "pTMt"n. lali l'" Iht·l'mt..."lr..lic..l _ I'"U,, · n -blio,,"";!', TI,,' l" I" n, llt is 11K' lOtU ,,' _ 11.... i n Fig. 2tl--J. "a n ,,·I~', 1110· 1> , fit "f 1-::'1 ' I lol l.. · , I..t". S ,lt.·
or
" 30 ill
."" 20
j
thai tI.., n",pc"''I(' ,It. os
,,,It
I..·... N . W·
;IJ''r'n ''(;.. lolt· until a ("(wK.1" d roilioN, ,>I' ah..tl i 115 ~Wl , b l'n... ·1I1 ......111,..1.. limitill!t o~ ....".· is ;q'l",0",11 ..l",.•.
-
~ 10 8:
..l....d
I ~ ~WL
(• •
ho "
"iI l--tt1J' I..h-
It-Isof 1'" '1>Tu l"l" t 0 - '>1'" lfiI)·m!: , ,,\ loti,,,..I·"'It....... c....1.." ....1
•
o .l--'o'--f---_--~
0.1
10
Unbound Concentration, ~ gIL
100
CHAPl1' Il20
lIitrnus m:id t· aJlt's tll('sia a mi wbu did uot t'xhih il il se ries u f clin ical e ndpoint s Indica tive of Il'ss than cpti tnul iUlt's thetil' t:o ntm l d ll rill ~ surgl'l)'. III Fi~ . 20-5 th t· mean pl'ft.'('lIt prol... a hi lity of attain i ll~ Sllti.~ fal-tl)rf control is p lotted a~aillst tilt' mean a rterial alfeutaml couce-nt runon for ~n lllps o f pa tients u mlt' '"Kl)in ~ breast. lowe r abdominal. ur uppe r abdominal Sllrgl'I)" III l'UIlHI1011 wir h other opioill~ , lilt' co ncentration- r espo nse curve is u'ry shot' p in all tlm"t· ~n J1lps . In additio n . tilt' mean EC."o values for tilt' tli rt"t' slIrgi lMotl p r oce-dures we re ill ti ll' ordr-r, IIp pN a"do mi na! > lowN abdominal > bn'il-~t , ll1ld all wert' KIt'a tt'( than the ,.: C~ , vahn- n-qui n-d fo r S
nme Effects So fa r. ti ll' t' \ ilm ples l'(lIIsidt ,(("t1art' Ollt·S in w hich rt' sl)(lIlst· is sllslailll"tl us lo ng as ('(II\('(·n· trattou at III(' site of act ion is ma tntafned. A lth()\I~h t his is fn "tllll'nily the- case, oc c asion ally it is nol. Tolerance can develop. w ll('n'h)" til(' n ·sj)(lIlst· is di min ished wn h ti mt' for a gi\l ' n l,(lll('(' nt ratic)fI (C ha p, 5 ), T Il(' tiuw (,(IIl N(' of tok-runce can \"af)' From min ute s to weelcs. T he nu-chaniam fo r tole ranl'(' also car tes. It lIlay in\"ol\"e de pl e tion o f ei tlrer a n e ndogl'IlOll'l transnutn-r Il l' till' receptors 10 whic h d m~ must bind to in itiat e a resl)(lIlse , Tole rance Inily also 1)(· m ust'l l by •• homeostatic mechanism wln-reby. I h roll~h ft·("tlba e k co ntrol, th e measurc nw nt n-turus toward tl l(' p rt"tlnl ~ value. /\ n t'xa mplt· (If toleran o- is that a.,o;lxi;th"tl wit h tilt-' n -oeated administration of nico tine ( Fi~. 20-6), \\ 'lu-n nicotine is reudmmfste n-d .... i t hin I hr. til(' d r ug accu mulates extt'llsivl'i)', but tll(· peak ('a rdioa('l't·lt' r.di n~ rt'Sp(lllSt' appt'ars to d im in ish . If tilt" d OSf ' S are se parated by 3,5 hr . accumulation is less, hut tilt' peak It·sl)(lIlSt· is now Increased . These res ults ind k a tl' a rapid development of tole r ance to tln- cardroacceler atmg t'fTl't1 of nicotine , t he TIIt"t,hallism of till' W II' n Ul (,(' is unkno w n. \\11('11 ac ute tolerance exis ts, the rote a t wll idl th e concentratio n is dlilll,gi ll~ may he a'l impo rtant ilo; rlu- (,(lIl('('nt mtilln itsd f. TIl(' t·!Ted of nifcdi pine o n hemod ynamics Illu strates this last sta h-nn-nt . I"' ifl.J.ipi ne , a cak- nun channel hll l('ki ll ~ a~(·llt. !)(lth Increases hea rt ra te (tad lyl:a n lia ) andlowers diastolic blood pre ssllrt' whe n j.,ri\"en to patie nt s as a rapidly di si ll t t1-:rat ill~ (~dpsn lt' , Fi,g. 20..7 shows the dlan~t·s in IWllrt ratt' and h lllllli pn-ssu rt' , tf~l·t1 lt'r " i tl l tilt' ph'ma ('(lIll'('llt m tio llS of lIifl"tlipi lle . fo llo....i llg ,,",11 Sd lt-dllies o f i.\', ad ministr.ltio n to a ~n )lJ p nf no rmote nsi\"e su!ljt"t'ts. \\1wll it rt.>girnt·n is t'm p lo,)1"t1 t ha t pmmptly attains t 'iK, 20-3, \ 1" ,,,, ;art" ri;J <-'' ''...' .... I.'' li.. II- .. •• ' 1>1" '''' .. ·I"Ii/"" hi!" ohl.u"...1 fur .Jf.' 11I.."il. , "pi/Ji,1 ..n;dlo:< " il', d"rin!/: lhe- illlnl<JPI'r-... tr.,. P"n 1 in ,,;01.... ..r tim..' ' ' J"I/:i<.,.] Kn",." "f 1'''1;.,,,1$ ,I"nnl/; nil.. "" cniolt' "n." lhl"'a. nM' Ii",., a... II"""" l'ncli'1,..1fnom 1<:'1' I, ,,~i"K rl W a " foe "" an.1., ,1llu,., tlt'k .." ""..I I ~' ,,' , ' ral:i"!/:II,.. ..,Ii",al,'" of i,,,Il\'iol, ,...J j",li.. " h , nM' .....I" ..1i,,. Ill" '''l , .,.Ju,., uf EC"" ",,,I 'f fur II", Ilm '(' ''' ~.,.] pm,,,I,,..,,, ......: h"'I""'w'I' ( 0,31 ",)',11.. 21), ."wl "1'1"" "I"]"", ,,,,, (0.31 m)',l1.. 21) (U41 "'Wl ~ II), n ..· h..n""",I'" li'II'" III so'• ..re II... Sh" llL...1 [....."Iitli<"~' " f tI.., ....1....1;"'. EC!ot, •...JUI., (I "'WI _ .. 2.0 10'\ 1). ( 1I" Ir",,~, fm lll A,,",,'m., \I ,E" ""11:, C C .. \ 1..." .1<1. Oil., ",III Hum ,. " .G.I. : l'la, ,,,,, " "I1''1 ,Ir-" ti".....r ..Jf,-nlanil " "I"i.. '(1 In ~IlPl''''' " ' 1 ",I"" .. ' ''I' k-a..... lhMoi'' fur ~" ...r-..J ' !lllt" I)'·
A' I IK.,io..u~·. M,3fi2...J73, I ~. 11'1' " ... 1,11" 11,,, I,,'nni..il.lf l .. r J.H. 1.i1'l."'"Ild l )
!! 100 lower Abdominal Surgery 50
Breast _ Surgery
- Upper Abdominal Surgery
O +---.-'-'-L-~--~~
o
0.2
0.4
Arterial Plasma AI1entanil Concentration (mgll)
0.6
CHAPlER 20
34'
50
..
1\
40
10
75
.....,. I . -, • i __
30 20
80
I \
'\
•
I ' o
100
70
"'---.
65
A
60 55 -1--~-~-_~
200
300
o
400
~ 50
100
200
300
400
80 75
70 65
B
60
o
55 -1--- _~-_~
100
200
300
o
400
50
80
40
75
30
70
20
65
10
60
o +---~-_~--
o
100
200
300
Minutes
400
100
200
300
400
c
55-1---
o
_ _- _ ~ 100 200 300 400 Minutes
F ig . 20-6. ~Iean blood C'OTlC'ffi lralion of niootine (k>ft panels. hue in color) alKI the eorrespcndmg mean Ik"art (righ t rands) in t"ight subjt'ds art...r two 3O-min i.... i"fusKH's of Z~ ~glminl1r is the irlC."n"tif' in II.... plasma ~Iralkln. but lhe grt'llt..r the maximum n>spon... folloo.\;ng the S«OOd dose. Tht- efft"ct on heart rat... is cll"a~. diminished thO' doses qnickly folki'\..· ~ oeber. a phel1OTlk"TlOll called tolm:n«. (;\ daptt'd and f{'(ITlI\'Tl from Porcbee. H .C.. Beno<.itz. X.t.. . and Shei.llt"r. 1...8.: ~namk modt-I of tolerance: ;\pplkalkln to nicol ine . J. PharmacoI. Exp. Ther.. 244:231-236. 19,>.'). :\ rl'IC'rkan Socit:t:o-for Pharmacology and Expt'ri nW'ntaiTherapeuncs.J rail"
\\n...n
n...
am i then maintain s a corwant p lasma concontranon (n -glIll" l1 I). a ~ mt
~~
j!i:G:: 80
0
20
' ~i_ 10 lf ~
tH£
2
A
.
•
4
6
, 8
~~
2"
10
B
0
I 0
.v ~
0
~§.
-5
oE
o.
2
4
6 Hours
B
10
"
C
.~ - 10 - 15
If,,,
g~ m
I
0
2
4
6 H...rs
B
10
"
. ·iJt. 2U...7. 11,,· r..t.·..( d"",,( .. ,,£pl"m.. (,("K~ 'fllr..ti"" I"''' I..· .. " u j<'" ,1.1,·nll;""'" " f " ...1'.." ...... ;(., '''·III..,,'l r.d,~ 1 IN'"' i th tl... 1"'nn!:-llOOlIli(' <'Il,'(1' pn"hltl'(1 ~. nif•• lil""O·' t:. d , " f .il \ ul'jt"(1' "'wi",,1 nif,..lipill" in ,1l.•till'1 " '):in ", u" t>o-1, ,IifT,·r..." t ............0 " • . R''l'im,'" I-_ hy ""...... of .. f,( "" p'JI,' r-n .ntrnllt..1 i ll r"'~M I ''' '' ''I'. lh,· r..t .. ....... ,..ljUl,lrd til illl 'nt'(ll;lh~' all;&i Q ;lI,,1 II...., mai lltain .. " ·Iatn..l,.· .. ,,,,t..n t pl... m" "M It... " lr.. r;otl fur iL"i hr . Rt~m,,,, 11 ..."ulant·...l" inf,,';'It] .. f 1 ~1 "'''''If fur lu hr ..1 1,;1:1, lim .. II,,· illfll.io" rat,· "'.... iIK'tl·........1 10{"Id. lo 13 llI ~r fur III min (ti lt' ' rintl.lM"oI...I I", 11 ).. -\. tilt· pl om.. ' lll>t-l· lllr.din ll (, l .ln n .. \ lill'· ) in III It' " ,1'J''t:1 .......,,;..,..<1 ",1lh ~ "It·t1. J (. ' ltl ll (0). H illltl C. tilt' tUIl'M!""" ll1l( III" ''''' ~lt l l' d ... ,,~ ... i n I,,·..rt ,..11,- ;II1t1
"'PI'" ""'''' ,,,
cli..." "lk hl..>lI I'A"'l"A·. A"I ."l11'o1·~" n.....1<"". 1.t.1'~"" ...,.. ,.;"'1< .. 1" ill, n"):i""''' II ,..., .....1.. fodl ill ,!i....,,,Iit.· h1tu I I'A"'' ''", ""I ,•• t~~ '~"·"Au... ""I"·A·'" "ill , A'j1;illlt·" t. tilt· ...>Uno....· """'" ,,1"..II...... i . II..• .1""'1' rl ...· in ..." .....Il l r .. li.. 1> .. ,.. II,, ·art ,...1,· ""I..·" tI", i" f",i"" r .. t.. ....... In<"fl''..... -d ..t...rpty .,,,1nlt>fl"·flt..ri~· .., tI,,· ,·,..1 "f "";" ..·u I. ",.(,,,,. " t ,id. ,1,,- pL.."...... "... ·ul r.. li..". 1"'"1,,,,,,1hyII,,· "... """",,·n. "1'", IInllilrolhlt·. n nlt't:I",ni.m fur tI,jl A1Q1I1t·n I'11r1" lt·'ll'lLff,·A·rK. · JI".I,,,...I I." nif...lipi'... i. 01:111 'Kot rul~' 1Il"!..",, I I..,t "",~·I ",,, ,,""10'11 with ,h. · I> I>\(' , 10..1 lI\(·I",rnn"l"'p' '''' n·ll."\ tl> .....1..,,1,,, ,, dlal'R" ill ......·,.,....... ,_. bLdil... "" .I"......1,,~, I>if. .. bpirlt· (1 "'WI. - :l.!I IlMf. (Fn"" " It~ n hl. .",· rn . <:' 11.. \'lI n Iln llnnlt·I.'TI. D.• 1>..,,1,..1'. M.• Fa"" ". II.. Unl"llaTt . J. ...ltl Bn ·illlN . U D.: H.." , "I' ;,It.,.,· '" ill ,I.., ,,1"""1<1 ,utlt..-lllmti" " ..f " if,..bpir" "win,. ,1.'l,·n ni"alll "fi l. I,,'uul:o,...mit: dT... 1' i"I,,,,,,,,,,•.cn., 11 n".... >I. Tber.. -IJ:2t}...."}tI. 1 ~7. ",",m""k~ ..I ;tI ' llt·n ni"it,.. til' C.\'. \ 1..J~·.1
ft.,
umlt' rlim' tilt" 1It't't 1 to complement ba seluu- ~ 11lt li t,S ill lI("alth~· ~ lI hjt't1 ~ \\; tll ~t ll
RAPID DISTRIBUTION 111t· 1111.\( '1, duranon, inlt'lIsily', and h lllt' course o f " 'spou se an' n-lun-d 10 tln l~ di sIMI'o iliou . Fi rst t'o nsidt 'r drugs \\i I1l 1IIJ('-<.'oml);artlllt'nt d la r.Il1t'rh ti(:s. For tlll'~' d m ~s . di st rilmtinn 10 Iht, silt' of .It1inll is so raptd n'lat in ' lll other killt' tic t'n'lIts Ihat. t·fTt"(1 iH·ly, a const ant pll.lpllrtiona lily, alwOly"li I'xisls 11e't\w'("n unbound dm )!: in pI.L~ Ill " ,1Ild ;.t l ilt' silt' u f action,
OnHI, Duralioa, and blltllsity (;i\l 'n til(' llIan y t"t ullp lt'xitit'S dl"l t'rlll illill ~ tilt' temporal pallt"nt of n "!oopOIIW, ("t lllt"t'p IS that Imn' un iyt'l"ii\trihulioll . \\111"11 a ll liSSllt"s. i1K' IIlt Ii Il~ lilt' silt' (If 'lt1inn. ;tnd n 'S[III11M' im mt'l liatl'ly n 'l1t"(1s tht , t''Unt''t'lltmtiou u f t1 m~ otl till' silt, o f ,K1 ioll, IIII' rt'lali on sllip 1Ie'I\\1"('n du rat ion
Sill1{'~ Holu . f)olfr , (;omitlt'l' a tlm~ Ih,lt t1i\lrihult-s inl o a \1lllllllt' \"" is di minah'll hy fi"t -onlt'l' lilll'l it.... am i is dL
34.
CHAPTEt 20
2 Eventual jy, a lime is reached. the duration of efTt'<.1 (t d ) , when tilt" pl a.~IIl;1 concentrutio n falls It) a value (C ...." ), !)t>jow which the n'spelnS(' is les s tha n th at minimally destn-d ( Fi/ot. 20...8 ). n il' relanouship between C..,;.. ami t tl is gwe n by app r op riately !;uhsli l llti n ~ into tlnpn-ccdmg equation. thu s. Cm...
Dose e - ~' Id =v·
3
Upo n rea rra nge me nt and taking logarithms. an expression for t tl is obtaine-d. 4
whe re e...... . " is the minimum amount needed in the body, A .." ... Al1:o n ling to Ell. -I a plot of du ration of effect ~.ti nst In do se should yield a straightlim- with a slope of lJk and all Intercept. at zero dnranon of efft'1.1, of In A ...... (Fig. 20 -8 , Inset ). For cxamplt', the duration o f e ffl"t.1 o f m all)' local anesthetics is p roportion al to the logaril lull of the injt't.'tl"(l dOS('. 11l(" 1II11scl(· relaxant ('fT("l't of succinylcholine co nforms to t l.i~ last equatiou . Figure
16
Duration (half-lives)
4
8
:iF ~ 4
1
lSi? .-.SE=
0
~
-0"" 0
::i:~ ~
/
3 2
+ 0.5 1
2
:38
Ci~
:28 ~ ~
2 4 8 Dose/A.... (Log Scale)
16
::i:fi ~
w ==
0.2 +--~-~--~-~
o
246
8
Time (half.liveS) . 1Jt. :!O ~. U" natio n of .... po"'... ill • I,:,' ,.. Il' 1...1(·1;(.. wil l, ..•••d , . ~ " ,ltlltl~ o ( II,,· .10",· ..., \ ~-t.·no" "."I I,:,' tI... ilK·A • ill Ii" ,.. A"I"iA,,1fur ,I..• c..'K -ut twlll lo ,,"'(·Iint' lu C_ (p>q>h ,.., ~·fl j. Dur.d i<.., i , ;
,.. l U---H ,huw\ till' lillII''' til III iT ln), C)l ) ( T.~, ). ami !.ll ~ (1',. ,) rt'( " )\,'~ of lIlu'>(·I" twill'll (;. un-aom- of III 'UnJIIIlN'ubr " ItIII aft " T ,tilllllbt illll of a lIP"" ) fllll,)\,ill ~ i.v . i ll jl"i 1ioll\ IIf n..'" , I · , 2-. .1I1<) 1 "II~1.: h..111\ tI..,, ", IIf \ll l'(;lI\kh.. luu-. .\ .. '·')Jol ,(·!c"il. till' , I"j"" III., j .. ind'lll 'IIl I"1l1 tlf Ilw l"uciplllinl dln~·II . Wllidl only 'inllllt'!K1 "; lilt, \';,Iu" IIf . \~,, ~ , 11..... ;llIlO' flf
[rutu till" ,I,,!,,,, j\ ().2 ruin " ' : 111(' half·lif,· i.. 3.5 nun. To fllrtlll' r ;lppn 1.;;I!l· IIIl" 1.'\1 "I,,,,liun . tllu"j.k·r tilt' f"Il, >"illi: ..I ;I!l-lI wnl : ~ 1 )u r 'lhulI «f t·fT'"(1 uan..,......·\ I~ IIIU·!ldlf·lif,· willi l"aI:h ,Ioubliug of 111""-,- n Ih 11111\1 b. ' true-. Tn pn",Ih .tI II i ... 1..-, ;j ~\"t'1I d ,,-,..,· O u Jlmdllu· a dur.ltiu/I of (·fT,·d. t J • \ \111"11 :2 ' /Ju i\ \0 \1'11 , IIIl" alllCltllll ill till" "u.. l~ fall, I ~ o IH·-lliUf ill filii' !Ialf-lift·. Ihat is. til lJo : 1111' dllratlull u f ,·0'..(1 11l;'1IIHI nllt · h a lf-Iiff' 11l1I,t III' I J . 1111 ' tu !;U dllmtioll of 1·0"'(1 rrlll l llt~"( I I ,:, tI... 1.1rt:l'r . 1.1'01' h . Ih,·n ·furl ·. ' I '! + t J . 'nil" ill('n ·.lw ill 1111" duranon of ,' 0'1"(1 1'. Iht'wfurl·. ",II' !I••lf-Iifl·, For ,·ulllpl••. .I.' ll ..'i 1I1~ ~ ••f " I( 1.ill~ 1.1."lm.· n ...lilt s in a T ill of 4I lJ ln "III I.tlt' I~ , .,'j 11111I . II..· c111r.lliull of .· 0'."(1 fj,lIn\\ill~ I m~l\;~ i, ., min l F i\l:, ;20-9 l. 1111' ill.n·.....• ill IIII' 11I1II' I" rt1.U\l'r. :l .,'j min . h IIIl' h.M·lif, · u f ,,"('(i n~ khohlH' 011 tht· sito· flf ,..1I11n , B~ ill'I ...1.1 ill\l: 1·... ·1. " fll ... T I,.. T ...... 11I.1 T.. , ( 1 1"" '" in Fi\l:. ;20-9, il i, app,(n'lIl tl ",1 1111· "'.. ,,, . ' ,1 h .. " I.lill.... 1U II IIOllhlill~ Iili' lit"",·. .\llIlt il'lr Holu. IJtnlr •. E\lo'IHlilll: II... I l tl r.d ~ 1Il uf 1·0'(1.1 I ~ illt'n',I,illl: 11 10' litl'ol' r.lpi l! [~ n "'lIlt .. ill a .~ 'llI l l t ioll of dumni..hilll: n -turn.., I ... pt '(iall~' (or a tlmt: \\ill, d , IHII1 h.M-lif,· .mt! d n;lm l\\ Ihl 'rd l'll 'IIIit: iJHL.·\ . Fur 1·\.;lIupl.·. \\11l '1I dllmlM>II of dT,... 1 i, " \1o' 1I( 1,, 1 1~ t m l hOllf· Ii".... IIII' '11l.I(IOIplt'tl 11.1'01' n-quin-d " I.I~ prue.lll(1· too t:n ·.11 "II initi .J rl...!'IIIII...· ..r 1II .1~ sul )',t,,"h;tll~ illn' ·.I...· IllI' dl.lllu · of t01,K,~ . \l llh ipil' \ 11I. I" , ·a · th t' '1111011111 in IIII.' 1IIIIIy alway!> Tl'l lIm, It. till' ,"11m' \ 'alll ' ·' . \ ~'w I,,·fun· tl... I ,t do... · i, ~i\t ' lI , ~ lal, 'tl t1 ilT. ·rt·nl h'. frum IllI' ..."" ..101,.... · , Illw a n i. dll rill~ 1''1,·1, t111\ iul: iIlIN " al . IIIl' ,1111011111 lo,t 1''1l1a'~ till' "I;...• J.:iH·II.
k , ,... !i IIMIt ,!
;;-
!
20
H e . 21t-lot,
15
1m.. p.<•.&h.." " """ • ..,,,,,,,,.].,, 1I ~ . ~'I:o&nll"" ,"·11,,· ,,,..... m''''1,,,,1 l ~~ T.......,,1TI"I.... IM' '_I. ~,Il, ... ,,1
E
10
~
..01.""",,,,,,,",, ..
~
>
Q
U
5
~
'"
' m w ,,, ....... ,.• I.. ~" .. ~.",,~ ·I~,
II I'l ..... "'·n· ,,( ""..,'1.' " ..h-l, (.. " ~,",. "I ,I..· '''''''''' ,of .. "I"m , ,( "" ,1.., h" M' '' ''I ) -/\••1._,. f.. ,," II... n(',n ' I,;, I ~ (; I.""." ," I "".. 1" ..11ml.-I.... ""· Ul ," , J 11 ,,,, 'Wi 'ih ] h'o7_1 , I' ll>';' 11..· ..n('".oJ ,l.oI ,, ' (,um \\'.oJ". l. ,,,l l hl~,,, J K ( :1"' 11'".] ..,,,I,,...
~
;:
n~·
"r
0 0.1
0 5 10
Dos. (mon
50 10 0
"I<" 'lh~ld,,,llI'"
2~:l7Z_r.Ii .
I'#>7
..1,1",,,1.·
' r"·.. ' I.... It,I,,~
'50
CHAPIfR 20
CL'.="'~ •
.2 7;; ;:; C1
• • • • •
"iii l::
.!!
•••••
.
2 46 Number
2 46 Number
of Doses
of Doses
.2 6
i C
8 4 ~
o
E ~
Time (arbitrary scare)
.'111:- 20- 10 . Iiotl, ,I.., ,I,mdio" .u .. l tl..· in t"mi l)' of" "";011... .1 n...' '' ..' · ill. n ·.......· "itl. tI... ... ~.."t1. 1",1 , MIt ...i ll. I....... ,It ~ "~IC·n ... -11 ,1<.... i, ~in·" . itl. lic:ah..I I,:\' an ..m -,ill II.., l in..' till' c·lT,..1 (ur n " K't'1,l r" Ii..,, ) R·....~ ...... pn..1t1.·m 'ir 11t'\1·L ," I""~ I 'It'''1
COMentration, Intensity, and TIme All ('!Tc'(.1 subs ides when conceutration at thl" sill' o f action falls. lI uw tltt' intr-us itv u f rt'SI)(JIlSl.' va ries \\i tl. tiuu- tln-refon - depends. llS does tilt' d urat iu ll of c·fTc "(.1 . UII dose ';Iml rate of n-moval Frum t ill' sill' of ac t ion. It also dl'pt'mls Oil till' rt'¢on of the conceutrattonn "powi(' CUI" ,' cown-d dllrill~ tilt" d.'c.-lillt', 11 1'1"(', di <;.('1 lssl u n h !illlilt'(l to tilt' sih liltiull in which tilt' couceutrati on-rcspouse rt'la liouship is maintaillt'(l Si ll ~ th nlll~h n'~iuu 2, n '~ I'M lllSl. · d ' 'l'IiIU's ill an almost constan t mit ' of :2211/h r. Tln- n ,.L\(lII for this cou stunt <1,'(,lil1l' in n' sl'M IIIst', ",Ilil,· lilt' pLL'illla coue entmt jon dl'(·!int'S ('xpelllt'litially, is appan'nt [rmu III(' iu\('lof Fi ~. 20- 11. I M ,(~l llst· in n w un :2
CHAPTU 20
3Sl
Intensity .. m' In C + b
5
wlll'n' //I ami iJ an' tilt' slop,,' and tnten...·pt of till' n ·laliumhip. Sllhslilut ill ~ C(o ) ' (. -ll for C ill EIJ..5, wlll'rl:" C (o ) is 111e concent ration UpOIl t'l1tt 'rill ~ n 'W01I 2 from n'W01I 3 , 1I11t1 (~)Il( '(1 i n~ tenus t1w n ·fon · )i eltls: Intensity .
1m · In qol
+
bl -
m ·/r: · t
6
l .. ·tti ll ~ 1(0 ) IN.· IIll.' illlt 'nsi l)' o f n 'spo n"",' wil('li 11ll' (UIlt....-ntrution is C (o ) IQ't·s Inlensity •
-
~ol
7
m ' /r: • ,
Thus. tilt' i lltl"~fjty ofeffi'rl faJL~ lillmrlYldll. tim" ill n ",oll 2. ~olt · thnt tln- mh' o f decliru-, III . k. dept.·lId s on !Iolh slopt.· of tilt." illll'lIs;t)"-ln l'l.1Il('l,·nl mlioll ('I.,I'"\l· ami half-lift· n f tilt.' { I m~. In this in staue-, for example, III "" 3 1 (ill n woll 2 til(' illlt.'nsil)c· of n ·spoust· dl;U1~t.·S by 3 1% of lilt' ma.\ imal n osptlll""" fur ;I I-In t.:han.t:,,· in C ). alld a.s J.: "" 0.; hr- I. u t.~ms l'Ul I rat e o f 22 %11" in lilt." de(·lille of ,1l1ivit)" is lIutidjMtt."t.1. Bt.')und 5 hr. when tht· concent rution h,Ls fallen llot·low 0 .3 unn ami "'nlt -n-,,! n WolI I. Ihe fall in n ospoll 'it.' paralh-Is Ihal of d rug. III 1I.t.'II)·, tilt.' half-lift' ('lUI lx- t1dt ·fJllilJ("t.l Imm iutensity of n ospollst'-lilllt' ILltil ill t1lis n -ginll: lu-re. half-lift· is II,,· finn- fur iUIl'II"il)" 10 fall b)"OIw·half. In prdl1k...-, l lot 'ill ~ dlls(' III a n uiahlt.· haselim-, 1Ilt.·,LSIIIl·lllt·1I1s in th is n "¢1ll1an' ofh-n Ion illlpn"t.;st· to permit accu run - ;lSS('S" UW ll t o f tlu- half·lif(·. TI I(' fon~lli,,~ t.'il"il liulls
II
2. 11)0
10
~
~
80
E
E 60 ~ 40
B
ReQion
"5
1
2
3
oo.".1==--:oc .3-'--,3,----~10: Plasma Drug Concentration
2 Region 3 .Region 1
Region 2
o
2
4
3
5
6
7
o
Hours
..
. 1jt. :W... I I . n", .fo·d"... itt II..· il1lrll,ily tlr r' rn..... *~· tf."'1 "" Ill tin ..·. r"IIo""1ul/.;o ..,,1/.... t..r.:<••1....·. I..., th...... 11ot,... . u .....""\.. "" I;ul/. 1.. 11... .. ~ >n' "f II "".·nlnlti" n ·n....p''''..·•.,,,.. liu.. 'f l. I nill ",lIy. '" n"jtit'" .1. Ih.. n'I1"''''' ",I"..oot """s,,,,i1 .10",,\,,'.. ;0 ~'l- f",ll iul"" U""""' r",tiu ,,n,,·n.,.f,,"r. ..' 10",1/. ii' II,,· ·nl n.' '' ..' i. "'1110;" 2. jnlt·".. I~' "f rt"'t!" Io·d " .. ~ "I'I'" nim"h-~·lin.'''~ ",,11, Ii"..·. ( h' ~' ",i ..·., u" ' l nali< ..' f..tl. In' n "1ti''', I .\<".. ,....·li l... III ""I" """ l nJIo.ll..... tI{ .1"'1/.111 tl ..· !""",. nIt·(.".....l1lr.d" >n-....I""" ·1..,,,. ,.1111' i . ... I I>;', E'I' I. "" 110 H :"" - 1 ...,,1"'1 _ 1
""'i""''''
·Ii,,,..
""I:l''''
. 52
CHAPTER20
art' exp n 'sSt"t1 ill terms of conceutrutto n. 111(' <-llm'sp()lld i n~ e-qu at ion s using doSt, ad minIsn-n -dand amount in hody are olitaim-d 1Iy llmltiplyi ll ~ ('It(' t. rt'Sllldiw co ncentr auou term hy \ Ulllllll' of distri bution. Th e nume r ical val ue o f h also t:hallJ!:l's .
111{" (,(lIIl"l'p h dewlop-d i11)()\'l' an' now illustrated with d(~rt'(' of muscle p aralysis pmdUl1:"t1 by Slll'(111)'ld IOlillt' . Cl m ll~es in dt>glft> o f muscle p;.t ral)'sis with ti me, follo\\ing a n.5 lllWlg IMIIlIs duSt· of s ll(.'d ll~-I(.'h(Jli llt' to it palit'nt. art" shown in Fig. 20- 12. TIl(' I -m in tlday IX'fo n ' OIlSt·t of (·ITt"<.1: i .. probahly accounted for by tlu- !IUll" required for hloll() to d R:lilah' (mill inject ion silt- 10 IIII1S<.'1 (· and . in part . by tilt" li llie for SUl"l1llylcholinc to d ilTlIQ.· int o til(' m-umm uscular junction . 011(,' (' at till..' silt', however, full rt'SpOIlM' ensues p romptly. tile turu- IId "'I'1'1I CIIIst't and lol al pa mlp is is less tban I m in . Total pa ralp is is th en maint ained fo r a full 2 m ill despi te th e contin ual rapk! illac.1i\'alioll o f thts aJ'elil. Subsequently, tile d TI"(1 subsides. As pn- dtcted. !M;'tWt"('u 2( )'l. an d M>% of maximal n 'spm lst', th e dTN1 d ed im 's at a l111lstanl rate: ill l!Iis inst an ce, 22 V lllin. At h i~l lt' r doses . the duratio n of e fT("(:t is IlIn ~1'r ( F i~. 2U- 13 ). b ut OUt" SO% of maxim al n >sponS(' is reached , Iht' amo u nt in tile hllcl)' shoukl 1M;' lilt" same andthe sulecque nt m it' of del 'lim' (slope) in int ensity shou ld he constuu t. 1111s is im ll"t'(1 so , K ll ll"i n~ !M;llit th t' rete of dl·t:lilw (m . k ) am i k [fmm the d\l mtioll -l l ~ dClS(' 1"11 11 , Fi ~ . 20-9), tilt" vahu- fur m , lilt"slope.' uf lilt' Intensity o f ti le n'spcmse I ( ~ (ilIllo liul ill hudy ) ('1I 1"\·t', ea n ht' t'lllt'lIlah '(l; for sU<."(i nylt:bolillt' , III - lOR It is th e sho rt half.lift, (3 ..5 min ) and tilt· slt"t-·p resp onse-dose cu rve that mak e s llc'ci n~kh()l i nt' such a llM'flll a~I 'll t d illic,;l1ly. Ch all~('S ill mu scle panJp is ca n he produced wtthlu a [ew minutes of d m nlQ n ~ all iu fusioll r ate. whic h allows fiul.' and con tinuous cont ro l o f n"Spolls(~. Also , OIll't' IllI' infu sion is stoppe d. 1!It" pati ent promptly rec ovr-rs. Oth"' r '-ItMll's o f Adminidnllio n , COllu'ntra tiou- in!t'ns ity- ti mt' n ,latio llSh ips after a sillglt" i.v. holliS doS(' an' ('1I:))("('1:1't1 10 hc' d ifT(' n 'nl Ircm tlloS(' St "( ' U follcl\\ing olhe r modes
1
C 0
"in
~
5.. 100
I
2 3
I ..... -.--. • • •'. •
"~
-,
•
60
c 0
~
~
'"E
• •
40
j
E
I
I
'.
•
~ ~ ~
6
•
80
u
5
II
~ j ~
~
4
~.,.,
•,
20
"~
•~
~
'"" ~ ~
c,
0 0
2
3
4
5
6
Minutes
7
8
•'
.• 9
10
11
12
. '\1(. 20- 12. C h....,\:.... in I h., d.ltn... of ",...dc' p"'• ..:Jp;' (a., ...........d ... tI....uptm ...u..n n f '" f\<.'ild . p md 'M'l't1 tIl " "'I. 'Il\(" In IIlu",. , h ", ,, Lthnll ) f..I ~ ...inl( ill . I. "oili. d, t\t" fJf 0.5 mJV\K1lK"linyldl<>Iitl<' 10 II. ,,1'1 '1:1. I. TIm..
''''1'\'''
of 1"1'1:1.. ..., 2. ' m..... " f tv.1Id . " 'I'1.........k.n : 3. I.""p
t"1 td • •"W,...... k"n: -I, S. .....1 fI , n'l:" " 'r,' 0( ho11d, tn 10'lt
,noW"""" rwtld.l.. i~ l . n... IInoiK'" lillM 1'1....... . tI.., rr,cio:lIlS of n....d m um n.. 1""'''· \11I.ri...."I...:I ..,1..,...1 line) .....1 ,",'11\'''' tI... ~JI '''' ' -Ii..... {I. "",...... -1 ..,.. I 6) nU.oIly Ii.......ty wt,h
(T 'n l, ;'jll'f. IT -5<' )' .. JIll YO'~ {T .,.) ,, ( 1111'
h llll' (,I.·d in;,,!.: 1'1 .1".... 1 li' II' ). { ~ ".Iif"'l:1 f.." m ,,""",•. L. t' d ... >Iit..·. l u lI.. d .."' it* IK\. 21j:3 7W 76. 1Yfi7.1
"d l)il"lIl . J- B.: Clinical .tn. I
011 ,uITi n~ldlOli ll"
of adllliu i~lralitlll . A n'C..'lIfn ll~ llllto"Stiuu for dr ugs of sho rt half,lift" is wlu.1her ti lt')' an' l a-st ,ulrninisfto n 'tl ;L~ mult iple-dose n~lIlt' ns o r as constant-ra te in fmiolls . There is no ~l"nt" ral ,I1lSWt' r, hut it h Iikd,' t ha I tilt" IIUl(11lllt Omav ht' di!Tt"n"nt . ("'\"\"11 fo r th t· Silmt· total t!.aih · dost·. s ud. a t1i lTton'Il~" is Illustratr-d ill Fig. with lilt" diu n-tjc fun)S('mid t> ( ha lf. lift· is .lbOIlI ~)( llI1 i n ) , T Ilt' saUlt' 40'JI1~ doS(' is " t1 ministt n ..1 a.'> a si ll~l t· i.v. ho hls and folll J\\ill~ an S-Ilr (1)1\sta lll ran- nf infusion (4 mWllT) aftt' r a loil(lin~ hollIS of S 1l1 ~. 11 lt" nnt u n -tkl·tTI"(1 is dtOarly ~n'a lt'r a fh-r tilt' illfllSion as is tilt' diu n-tjc t·ff("(1 (S.H ,"S . 4 .6 L of uri ne in ~ hr ). C II·ar ly. concentrauou- respousc-ume n-larionshtps ca n hI" mo rt:' complex folll J\\i ll~
2o--J.I
o
100
. ' • . 2~ 1 3. Im "'l" "l'tiw of I...• " f .....'("j"'I. d ....i' ", lnoini.t t' n ..J, u,...... 911'l of m i" uJ l"'r.J )~ i5 ho...I, lI... nol .. of .I."-~i,,.· ill O1 '... .-1e- p" r.J p is i5 t'Olnt..,,1 ;al 22'lJmin. (1\,..Jr"",n fm lll tI,,· fiWlTI' h)' I A"'Y' G.: Kir,,-1it...,cof pl,~ n,,_~ *~ _in'i l ~' o f lt1<.'Cl " yld",hlrf' in ", ,,n . J. Pha rm. Sd., fm'" .5I'i 1&i7_ 1fW>. 1l*i7. n... ''"J:I"a1 ,Ltl" Walt•. t·.• lU"l l hl lul" J H.: e ll" " ,,] oI,,,lit n ~I "''' chl. >ri<.... A".. otl" ..... * ,!o"" 2'1:37z..J76. 100 7.)
n,,~ld",",i nt'
"0
~
~ 20 Dose (mglkg):
o
0.5
1.0 2.0
to
5
15
4.0 20
Minutes
500
. ' 1" . 20- 14. \I ."", ,~ "" "Ltl iw "n· C'U'n 'fit'" "i ...1", ,,, ,I"n nll: I'" "lor pt·rit.1 aflt'T ;a .l" lI:lr -'41''''11: 1...1,,,
1Lit' )'
400
.1.
°0 ,g 300
;a"
ss
... " ..' "" " "lIll .....""' lti\1·" ,tl,,' r"'., uf ,I.,. t"..'), Ilf f" o N 'mlcl., i. d, ·..ri)· a ,I.",·r-
~
~
~ ~
~=>
200
'-'~
100
e = ~~
I."", JIlat L" 1I:
,I. f,..k 1 hy llIl .Ii.hr i" f,,' I"" of "' "'WI,r "f f"mo. 'mit.I., (co l" ,."l lir...) ill
E E .,;
> .S :::: ~ -s E
(I,Lot·.. Iii,,' ) ;a,,,1 ;afl,·r II......."... m l lti n "'-~ lU ' ~"'II:
d !4'1 "'....'
","" ",I " 'n ,
AII I....,!4, II..·
"' i"" "1 "i ih .~m",LtIi\.. ""l " ""it' ,i-
f."i . (1\' 1Ir""" , fn "" ,".u, "I .~.-I. J J M,.
Soni" , I' ., R",...I, "' (; . ,,1., G.·rI;al!:. 1' (;
G.• T;an. l .• ;01,,1<:,,;1"''' <1,
1), " ll' lk .·fT inR .."'tim
Ir"t:-·oi
.· W-J.:
f,,"...·"'itl.· ,j"r_
",lml" i' lrAlit", ' '"''''''
I...." . i"ydioo ill 1....a1II,~· ...I" nh...n
0
e li" . l'6n"'.....
0
2
4 Hours
6
8
I ~l. )
,
n it..... .SJ,+I4l-1 44.
C>
SLOW DISTRIBUTION Til t· onse-t , dura tion . am i inte-nsity rdatiollShips art- 110 '\'" l1l1lsid" rt"tl for thoS(' d Ol~s th ai slow ly d ist rih ute intn tissues. A tw o -('ompart llll'n i model (C hap . 10) is j·lIlp h ilSi :tA."t1.
Onset, Duration, and Intensity 11 11' im p'let Hf d istribution kim-tics 011 du ration allli illk nsity of dTt "t.1: dl'pt: nds 011 twu [ill·lors: sp('('tl of ('(Illilihmtillli of dm~ at sitt' o f action and si...a- o f tilt' duS(', S i n~II' HolU'; Dose. COllsidt'r first the sttua tlon in which rlu- sill' of ucnon ts i n a nlpid l~' t'1lu ilihraliuj,t. am i lu-uce « ell-perfused. tissue. The peak l' fTed is M'(' 11 almost illll llt't iialdy afh-r an is. holus d o'it" il llll t llt'rt'lI fh'r tlu- (' !Tt'<.1 is di n '(1ly n ,11I""I;1 In tln- pl ;l~ lJl
A c
~
" ~
u
8
100 Effect (% of maximum) 90%
10
c 0
'-'
50%
2
10%
0
0
~
10 30 Dose (arbitrary units)
E ~ ~
a: .1 0
2
100
10%
10
50%
-c- 8 Eo
" '" '0 ~
~
6
c
4
~ 0
2
0
0
0 4 6 Hours
8
10
10
100
1000
Dose (mgl
"·il/:. 20.. 1 ~, D " r.. lio ~1 o f .·ff,...1 i, "..",... li''' 'arl:_ ...-jl lt II..· It'l:otril lnn. of.iI",,' ''''J:......I.. ·ll t h.· '·ff....1 ......"" " If "''t.1I i" t" II,,· " ·nni" ..II"''''''· "f a t" .rti" " "lIy f" r " " ..II i' '' ill .It"",. SI" ..." an" " ·"'ilt.,;:..ntl "" it· I,It ~ , .. f .i" " ,I.." ...I I.I...." .. (' Jl". -" lraIMN'-Ii "'I' I'" ,filt... f" r .lifT,·n"'11.\ ', 1• .1 ". ,iI"" "f it .Inll( II""
,I" plal' pn"..""..... 1", ,,hi'''I,,,,,,·nli.J ,1" 1" ..il it'" li 'l("tit.. (,ll. .11,,1 tiM' "'m"p" n.1inlt,lnr..li",, "f 0 1.."'.. ··"·,.01. · !t~ ,,,"". I,!tll:' f.., pn"'''·!t'rmi,,,...I .·,,,II''>illh t" rn"'I">I"hnl(In .lifT,·n""1''' ')(n.... ..f ,,,..d ,,,..! n...I..>I • (HI .
CHAPTE R20
3 55
til this lime fr.ullt" d m ~ l'i luilibrollt'5 Illlilt' mp id ly lx-twe-cn pt.L~ lIIa a nd ucun nuuscular jllnl1io ll, tile stn- o f a<.1 ioll . The R 't"(l\"t·ry." tilllt' incn-a,.... 'S pmpo r1iunally' with tlw le ~ilritlll n of tilt' dost, when tl. t' l lu ralio ll o f (' O'("(:t is well ill l'Xl't"SS uf I 1Ir. 111ls l"Illldi tioJl is IIIt'I onlv a l the hi~h('st dost's of d-tuboc urarine a nd wllt'll a small response, T»I,' is dllN ' n ;L~ 111;· e ndpomt. At 100we r doS('s a nd when a wr-a lt' ( (t'SPOIIS(', T ill' is {'hoS('II. tilt' d urati oll of t,IT("(1 is M'i'll to ill{,rt"l'it' d ispmportioll"lIy' with tilt' II ~aritl llll (If d oS('. \I ulti p t(, Do\ i n~ . Fi~. 20- 1. illusrrutes tilt' {·'1'JI.'l1 1"( 1 n -sults wlWII tilt· sanu- Si7.t· d IN ' is adm inislt·(("(I I"K:h tinn - (('SpOil S(' fa lls tn a pn-detcrmuu-d value, or when tilt' rt'SpOl I <;( ' h'L~ jusl woru nIT. 111l' s('l"lmll d ust' p md ul,,(os a l.i1-:h{·r l"lJIII"(' nt mt ioll in pl;L\ lIIa a nd a ll liss Ulos of tilt' IMMly a nd a {"Ilm's!'M lI1llinv;ly mon- in!t'lI<;t' (('SI'Ml!I'\(' than th .t! ad.it·wI I a fte f t he' first d ns(·. AISl), sillt"l' Iht· !t'mlt'u l'y for dm~ to n-t um from IIII' tisslll's is aIso incn-ascd . tlndu rutiuu of (·ITt'l1 is g n 'a h 'f t han afn-r till' first dOM' . Up In IIIis point tilt' n-sult is tilt' smllt · 'L~ expect ed for a dm g c1ispl a:"iug flI1(, -I"(IIllpart Ull'nt (·hara<.1(·rist il-,; ( F ig. 2U--9 ), h UI di lle'f (·lIl't·S do (·II\(·fJtt · on ad minislt'rillJt the third and sllt'('t'ssiv(' dIN 'S. O il n·I'JI.·ati ll~ ndmuustmnon a mi as d m~ in till' sluw ly t'i l ll ili hm! i ll~ tiSSU('S r ises. lIlt' I('nelt'nl, ' to t1 istri lmlt· 0 111 [rmu "100(1 a nd othe f mp id ly t 'i lll ili" r.tl ill~ tiSSIl('S diuuuisln-s.. \l,("II nli ll ~I} . tilt' du rut km (If efT('l1 beco mes p n~n"Ss i\"(·ly 1 01l~t'f un til, within a d()!\ill ~ interval . till' amount t'1im ina h'l l fm lll tltt' hod y equa ls till' dost· i.d lllinistt' I'l't1. O llly' rlu-n an' tl,(, ("I)ll('(' nt mtio lls uf d m~ ill a ny ttssru- tilt' ~1II 1l' at till' 1){'Wllllill ~ a nd (' nd o f tilt' t1nsi ll ~ inlt'f\ ul. III("( llJl rust In durution.
A
160
T~
~
§. c
? 120 §.
T~
il
""0
~
'" ~
80
T.
0
4
.~ u
c
c 0 <.> ~ c
2
'0
O! 0.8 0
~ 0 0
8
8
:,:
.,. D
40
0
~
0.4
~
E
~
'" e,
o 2
5
10
20
0.2 0
2
Dose (mg/m2)
3
Hours
rM, ·""..
. 1!t. 20-16. ,\. " ""1". ,I..... iI.'ll; ...,.Id ..r ,1·t"I........flU'ir..• !ti'..." j.\' I.. a I:n ..,p ..f ." I';...·h , TIAP T,,~ ""..I T '" ;".b l' · !oIl1. .'50. .....1 It'" n '(":M'''' "r "m..·I0· ""ild' (11 n "" · ,/ II..· IIr "1 ,,m "f mu.. -J.. r"",-1i",,). 8. S.·",iIoI(ViIIKIIW;·I'I.. I.,r ....h r".. h..:I"......, pl....""" d _I" I ,flU'ir ·. ."I....lio..'.li"... I'..,lil.· r.>l1o"'1nl: " O..5- ,,,w\:.~ t \'. 1..>1". ,10....,,( .In'l: I.. a 11:.. .. '1',,( 10 .,,1'1'(1<"
.,,1:.....
(...., R I
" rn NII L1... lili(ull' I~ Gil..J.b. \ 1.. I..... ~·. G.. .......III ;t~1 ..n . W.: Ki".1it"1 "( l"I"nil""I;'''1 a' .. I ,.....,r<.." " .."lar
hlt...-Iillo"'. l fl.: 1>" ....1;.'" "r at1i",n "f ,1·t"I".....'nuir..· . ,,,I Ii("'I Ia"' i..... A,..-.tI....ic.I"K'·. Z9 "~ l-l , 19M. ". ,..... .I"t"I..:1 with "'·nIli..;"" of p i. UI'I""c"lI. H: R' ' I I.."",' n [roru Ih.· IUla ,,( SI..';I\O·f . I. " .. Stan .~;' D,H. \" rn·h. S.. Mille-r. It l ).. ,,-,..I II","n. J.; s; ","h..,........ n.." Io·I;"I( ' /
l>lwm_~oI.i "' 1"''''
,,-,..I I.t...n"at'l K...I"'" tn
,j·tlll...:unuillt' . Clm. I'twml"",~ >I . n "·f.. 2.5:.1';.'1--3':" 1. 11r.9. R'l ," ",I",..:..:1"illl ",·n" i..iono 1/ CX \1". ,,:,·.)
""""""01=
356
CHAPTE R20
~f 5f'ONSl:
ts
6
~
'" ~c
B
•
•
2 3 DoseNumber
4
•
w
...- '" 0
~
-
~ ~ ~
A
100
-'"
2
E:i5
~
-
~ ~
Tissues
~
0-
S
0 1
c
~
•
4
2.0
10
c
'"<;" e
1l c
~
0
'"
,,
Q
~
E
~
'" 0.1
---- --- -------- --. --- ---------- --- --- ---
c
.;;"
, < , .,
~
0
1.0
~
0.5 0
2 Hours
0
• •
• 1
4
3
•
S
Q
- .~.
0-
1.5
w
Plasma
<> 2
C
2 3 Dose Number
4
.-II(_ 20-17. A. \\ l l
''''''''I1 IC''''
'''''C'f' nlratl" " "' P',<1...J1-11
' "k
i~ C"lq"'lil.. 1In in..""'".... .• nnly' "ilh ,ho· i lK"R"" _ t1na'IlIIti<'alIy' "1",,, tI,,· ti" ,,·
"''' h...·" ";"'" ( I. II. ' ,JoI,' II"" I I"' I" '''~ i"1'''''i1y ..r .. ~" ", . C . Thi~ i, in ...",' r..,110 ,I" r..li.." i , :O': "I it..... I.' >'\-' ,I" mli"" n ~ ", ""an "If n ",,~ inh, II... Io·nn in..IIII, · II..· ,~ " "~·n t r."i",,1<
,or.·rr,
" ltl ,
,I,,·
,or
Un,,' """I"W (W"III, A).
10
c
I
r,
40
n..",il"....1in .. ,,,101'1 " "" .....'"'''''1tI,n..· ,;0.,. ,1", rI-I.·.." i .v. inru' ion, ..ft h,,,,,.·nt..l. 11,,·
i, I" ... a,,,1 Ihi"I ........"
20 30
_ Infusion
o
.·r·
i . ,,~ n '
"" It.,,, ,,,), r", U '''':' '" Ir" ti" " 10 ran in 1''''''''''' ",w.l in r"l'iJJy.' '''!lli lihr''Ii''~ Ii""".. ,,"'h .... tI,,· hni" dimin-
1l 30
s '"
.·11(. 20- Ill. K"d, pl.., n", ...",n ·nl"' I"'" ,J II'i"I" " " Ial lei a,,,1 ' I""i r..l ...11...• (,..~, ..I ,.. 1.." ..1 lin"'. "n •· 1""·'".." II.l..'l/;r"lll,it.· " "'",,,,,' . ,( ",,,-st1"1if;-
•
o
10 20 30 40 50 60 70 Minutes
I.."'...· i<. 1'"* "'1:1."1. lI" tI..· ......."..1a'ltl ,.. ";;,,,..1"ill, tl... ri .. • "r .Iml!: ..'11.......' · I",li"" i ll ''''''''Iy' '''!IIi1il,r..Ill1K Un , T" mio",..i ", · II,,· in.... •...... in ", imal .. lT,..1. a1 ~ ,1"'1 1'".10 "....1 " i ll, tl,,· 1i"I (Jt;, 4 rn~ltl . tl "',. .. uf tl... No" ~U( ... ... i' " "n' n..It" ....1 if" S.~ m~K). 11,,· "" li,l li,,,' ..-10 to II,,· pLa. rna u" ....·ntr.at:i,," ' ,.)' ''''1 i, I ~ l'....ki 1(u".·"I..." h"" afk , filii"!!: ,, "it"I""""" ILl! ,h. p'" i' it'' ' n".It·1 ,.. tI,,· I'la.", n "...~ "l na' it ..,. Ii",.· 01:"... Ko'Cll"'" tl,i..I'.'flI..l I"'.It "1 a .li",i" lIlit'n '" ,h. · ' p"dr..l ...1".., Ih.. , ,"" i n! 1Jo:t -..It. i. in· wrte..1for ("Luit',' I I 1l1W1.• 4.11.1 \1 1. 1", lruwn frotn 11 ,1<1,,,,,. H J.: SI"",l l. 1>1\ .• slIi.I",,,,,. I.,J.. "" ,I \ 1<...,,,.,• •:.; A n""It·1ror ' ''Illyinlt llt,JlI, of "~ Il('~i" ",,,I "" ,10' t.>I.·r.......· t" tl'it'l"' lllal, A'''''t1 it,..'K)-'. S9,.3I11 ..,JO". 1!h5. 1I'11rtK1,u 'tl ..." h IK·.." i" itll' of
J K. LiP'I'i 'Kd
t.)
CHAPIEI1 20
inh'lIsit)"o f n 'spo lIS(' tlOl'S 1101 ill(."rl':L\I·IM.",u lI(l tin- sec ond dose. beca use-th e concentrat ion at tln- silt' of actio n jus t befon- t ilt' IIt'Xt t!c)St' is alw ays tilt' same. Tln- evr-uts sllll\\1l ill F ig. 20- 1S with thiopental are illllst mlivt' o f d os in g to a minimum d Tt'l1 . FolIl l\\ill ~ n 'I)(·t itiw· i.v. tlc lSill ~, tilt' plasma couceutranou dt'dint'S mort' slow l), and lilt' t·lTI>(:1 lasts 101l1-:I' r a ftN Il.t, Sot'l1Jml and thtrd doses, t'\'('11 th o llgh tl l t·st~ dUSl'S Wt·n.' smaller than th t' first to pH'w' nt 100 g n'at a n:spIJllSt'. The da ta wi th thiopental also ind i("a !t' Ihal tilt, hnuu is a rapidly 1''111 ilihratillg site . with a minimal t ll,LlY in wspo nse. In ad d it ion. tlu-se- l Llt,\ tin nul Sllp po l"1 a com mon stlg,gt'slio n that tolerance to the h)lllloti{· t·lTl'(.1 o f thiopental fM."{1U·S a("lIlI'ly, If lull'r.uwt· had IJ{,,{11ITt'l1. tilt' se nsitivi ty to thiopental " l lUld haw decn-used. it wo uld haveleeu exp ressed a.s ti ll' tuaxit ua] n 's po ll"l' is seen, even Ihnll ~h t he plasm a concentration is at virt ua l stt·ady state. I II ad di t io n, Upoll Slo p ping administration. rt'5POIl.W wears off sl(I\\'ly a nd ilia)' re main IIfJt i{'t':thl~' loTl ~ a fter tilt' ptLsn m concentration falls below detec t ion . In the a h M'lIl't' of sud . i ns;~h t , then- lIIay Iw: a tempta tion to mist akt'lIly dassi (v tlU' d m~ a s om- wi th h it -
and-run characteri stics . A IOI ' ~ simila r lint's. bi llt ljll~ o f tl m ~ a t 11ll' site o f act ion ca n <.'tlll{'l'i\~olh ly 1)(' M) light th at its n-ruuval, allll SllhSt'IIIlt'ut de-cline ill e ffect , is slowe r t ha n the n\"(' r-dll declme of dmg. in the ho(ly. Au l·xitT tlp lt· is t hut tlf tm-thot rt-xate , a ll ant icancer dnt!-"( tltal lunds a\i
10
~JJJ\f-rn01\1\1\t\---1Effect Site ~ e
1
Minimum Detectable Concentration -
~c
Duration 01
<3 0.1
Effect
',, '- ,
Minimum Effective Concentration
-, Plasma " ,,
,
--o
2
468
10
12
Time(arbitrary units) tI ll:. 20-1Y. \\1..--" . Ii_t n t" ltio ,,, In ;ultl r" lt" .·Iiminotl;' ,.. ..In'l: ill II..• Ii ..c,..' at,~ ..""Lh.. ,\.:.....~' "" ",,, hip\':, .Ic"'inl(. Thi. ,1t·Lo,"l lht. "m.1 of (·ff.'t1. ....,'" whna I.... . Irul( i, I(i\''" i.v, ,...rIN t1i '<:~.nh tlllitl~ dn l ~ ..l"'ini' t rati.." . Ih.· pl , ,,,a COtK'<'1lI....tkltl...-y '11IiN-J:.' ral] I..,k tI..· ,1c1.'(1ahl.. h",il . htlt nl~ Ihr lin..' .,.",rw or II..• .~ n ......'C r~I ....' . II., Dr"1llo: ,li, lnl," litln <1,..1 rt '
",,_,k," ..r c.v. \lc "I ~" )
K.""..
CHAPlH 20
(oncentration., Intensity, and fame T ime Delay-s, Dm~ rt'sponM' oftl'lI lags behind p];L\Ill11 eoncentrat jon. A st ri ki n~ example o f sud l a tlday is till" rise in l(,ft vent ricula r ejection tum- index, a measure lakt'li from an t'!('l1ml~lrt li u~r,lIn , whilt' IIIl" pl'L'IIIOl coneentranon fall.. du ring IIIl' first -I hr afh-r an i.v . ho llis dOM' of digo xin ( Fig. 20-20). Certainly. tilt'S{· data tlo not 1II1'.tIl that h-ss dnlg is Ilt't'tlt'tllo produce a gn'ale r respo usc . Rat lll'r. di slrihutioll of di guxin tutu l'lIrt!i"c tisSllt, is slow . Tln-refon-, to lise plasma couceutraticn a ~lI idl' to digo xin IIlt' rap y, Olll' shuuld wlIil llUtil distrihutlon l"t"lllilih rilllll with cardiac tissue is n-ached. wh id l is alMIIII f hr alter " dose o f d igoxill. On rd atill~ n 'sIMIIlst" 10 l'tJlll't'ntmtiou lM.'fo rt, 6 hr. a ll ab sunl n'lati omhip is oh M'nlt't l (Fig. 2()...21). 111l' n'SpO!lM' is nil when till' l'tll\('t'ntml iull is highest ami till' (1 )flV( 'r.;t' . " 'l' n ' till' n'SjXIIl'>t' lu 1M ' follO''''("t"1 \\;Ih lim e , il would ("\,'nillall)' (tl tys) t1t'l·IiIll' tow ard ze-ro, ;L' apprndlllatt'ti by til(' dashedlnn- in Fig. 20-21 . Following an i.v. in fus ion or an extravascula r dost" p lasma t1 m g conccutratiou riM'S ant! fall s. 111is llIay lead 10 Ily,derrsb in th e concentratton- n-sponw n-lanonsht p. 11 us eful di agnos tic o f the temporal featu res of drug n 'SjXlllSt'. An l'.x:u npll' of such a cu rve is shown
.t,
FIJt.
n...
!~20.
I rk~ ,Lcr
..fT.'O['f . i'I('ft"lI....-s I ....tic",
8
pml' lI1!:"linn in tl... Ie·fl w n· .,...1;.... lin..' j,,,Ic"$ (OJ. a " " ';/.." 'rt ' u( a'i
lhe· IJIa" CllI .Ii~ni h '''Il1k..,,,·
(cule,rt..J hn..) .1c'l1i,,,-s (.. r 4 lor
arter ;_".
of .. I · n~ .10 · or t1i~JXin . A",r• •141.. (nlln mud . nll;. 1'1 (I mltfl• • 1.3
", 1r"ini'(l>llic..
•
",M l.
(1~ ... b
"'1\ fn ll" .1..1.. o f SII>l("i'U. W .,
~ .....
al,ara. K., and Taulll·rt . K.: R..I..li ",,, hi p H( Iw...."'.. ,Ii!tilll'
H Jt. 2~2 1 . \\ l " 'n tl..· n",p' ''~'''' ,Let.. i n F'iJt. 20- 211an' Il'lah..ll.. II..· Iw...."' ,. ('(·nlroiliclll of Ji~lin . II.. • rt."po..,.. · ;'1 '1, 1,, 1.., hid .... ' .., II..· 1e" 1 ('t" I('('nl l>llic" , ..ne! tI... ("I .. " , .,...' (('(.I ..J Ii,..-I, n ... t"$ '
2
4
3
Hours
40
, ,, , ,,
1","p, oL!li" CI 10 11.(· " I:*,I is 1."'.....1 .·....tic·r Ii nl('S "'he· tI... ('l"""·nl r-. ti,, CI is h j~, . At
lin pn"...tl~' ",;my ,L.~"'i L.t..r a'i Ih .. " ..lr· M.. ;. ..h."" 4 4 I,r. n ·'llClrl..• "huClkl rt'fllm 10 ",,' m (.La. h....1 h,... on
1111....
,"'"".
,
, ,,
WIl ,.
, ,,, ,
•
.....•
I
o
o
2
4
6
Plasma Digoxin Concentration, jlgIL
8
10
""""20
'"
in "'i~. 20-22 fnll(Mill~ tht· i.v. infusio ll o f alfe nta ml. an upinill ;U1;J~I~k . ShtMlI in Fi ~. 20-22:\ a n ' tlw plasm a (''UIK.'t· n lrd.linn~ and 1h.' reduction IIf spectrul ('( I~l " ;11I (,I.'(:I Rx' n('l1lha]''''ra phi<.· IIWa.\ UR" of rt"!iPlllI~. in a \ lI bjt"(1 (ill ri n~ all(] aON a 5- lIIill illfu\ iUII n f 11K' dnlK. Ahl.ulI~11 then- is a stl~('St ioll of a time la~ ht'h\l "t'U pLt'III;1 ('"K't'nfr.ltinn anti "-spon..\(· (mill flJis graph. the tlt·lay is much IlK)r\" appa n-ut when n-llllllltht· n '\(' o ( al fl·lIla.1II1 in pk.\ma. SulKt"l:lllt'lIt !>', "...hilt- tht' plas ma ('01K"t" n lrdtic K I falls r.tpi d l)". Iht'n ' i'\ lill lt· d"lII~(' in (·fTt'C:t . On ly aftt'f 10 min do,,'S rt"SponSt" fol k~' ti M" fall ill p la.\ma ('u'K't'nlrahofl . :'\otK't· lhat d M' dlRmok~ ~" I IU'IK'\' of th,,' paired cUI}('t"ntrat ion·rt"Src m~' OI"l'J'\-aU' Ml-' lUI"'''' in a l·o llllll·n.-lnl·l." i ....• "lirrt1iu ll. Witt. a1fl·lllan iJ. as wnh man~' otl w r d m!:s, Ihis l't)llllh·n ·k,d l;· ~i~' h\'!>h'n"Su is most lil.d,' can ..J b\' ddan..J d istri bu tion to Ih,,' silt' of ac:1ion. Othe r loxpla,':"Uom fur (L.'Ia~ 1....1 n~pnn • ind; ldt, d~· fomwlion of an ....1 in · IIM1al. ,lih', ....1IK·1. t;di;n till"" to n ·"",11 all alL."JIWh· ('tHK...·ntratic:HI (Sl't" Chap. 21. \l d at-ulitl' Killl1K-S); 11.,,· sltuabon ill ....IIM:h th.. ohw J'\l...1 n ...pull ....• is an i1Klin'C:t nM·a.\lIR.· of tiM' true dT""'1 (st...• Chap. 23. Tu mo"N C..orK..-pbl: and the rondition in ",hidl t1K· ('t'IKl 'lIlr"tMIII of an (·IMS.,:.. MMMIS IlwlrriaJ is rrtlIK't"CI,IMlt onlvw IM·n I)"" ('U'l"'t"ntr.dltMI falls 1 .·S. ~· a l.,;til..J ,..Jilt· t11.'S a n·ar.1klll Iha l pm"llIl't"S Ih,,' oh ....·;."l:"'l! n-spon\(' h.....'OIlW rale.limiting,. !\ I an~' dn l~ an· lip,..bilil- anti equilibrate rapi(~' OK,"J\S ~,·II.I'.·rfu ..."(1t i\\lI~ . e .!:., lK~.u1 and brain. w hK-1i an' orh-n taf'l:d o~.ms. For t"'~· ti \\II('\. bec au....• 11.,,· p"'riod of ul~'r-
i~
1.5
"c. 20-11. .,\, T,n....m unr or I........... tIt.. in ,...."f1""<1n/ ...~ l "" rIn1n .......~'lU.."..K' ....... .. .re- "I rff"" .... II.. I...."n/ nrn."~ ~~rml "",I I &I1..n.1 pI.o.-n.. . 1 '",' 11 (~ ......'I nol...' •• ' ii,
•
hjn1 dunn( "'oJ f" U. , lI( '" 1..5 ~'mln inf,,· .... ..I -'fn ,b,nil f". 5 n,in h ..lill h.r l. 8 . t'r n.... n1 ....loJrtl<-. ll 'l'"1n1 ~ '""" U1rri.td rota' IN .aI.
" •. 1.0
'"
H
do..hi.,.
~i "2. € 0.5
rrfll....11
l01 ... .__n...." ..." >C Io:..,\, l"'tI..I oIy (
'_n
"1....• I I~·
,__.
n... 1I.m "'~
indK..... d .. 1m.. .. ~ I'IrTK ... III II " h ... n ...h . .... ( I m1(l1. - 2.0 ", M ). IFn ll1l !lcun . J C .. I""~ KX 1 ~lol/ .. 1d. ilK : t:t:C:.." IoI/. ltl odlO lI. "r , .
25
15
Minutes
(uh e ..IT 1 :
••
I'i'.'>cl,)
• 05
n ... (~ "" IWflII k" I~"," I_n f:.u.. n,iI
l
d ",1f" " I. '" 1. ..,..·. d .... i<>l.<~ . 1i2.Z,'l-42-4 1. IW>. ltoT'n. I"...... II~ 11O·n" i..iI .., "I J Ii U rf.. n' ",n,I
80
1.0
ArtenaJ Plasma Altentatlll
B
~
L.:-....I d..t nil"til.. .,( dn 'll: In''' ' 10
A
n ....-nl
Cooc
1.5
OWT!'" vanon ill dillil'lIl pml1il'c.· is ofh-n hours if nol clays . all~' time delay iUt·fTl't1 is Hied)' to IN.' minimal ;lIul dOl ~ in plasma ( P,Ul he com-l an-d dt rcct ly with (·IT(·(.1. Thls was the case ill th e study frum wh idl tilt" pm pr'U1lllul data in FiJ:. 20--1 WN t' obtained. Propranolol was ¢W."ll nmll)" in s i ll ~l(· .111(1 Illuhip ll' dust·s, and measurements ....'ere mad e OVt>f several hou rs. pa rticularly a(tt'r tilt" pl ·uk plasma U lII l'\'lltr.ttioll hat! lx-en reached. n il' statem en ts uho,,(" apply ('\ '(' 11 if dist ribu tion I h ",lI~h()lIt the hody hao; n ol been ;leh it,\,('( 1; all thai is requm-d is thai t1islrihulio ll ('qui)ih riu m I lt·~'t"t·1l p lasm a am i la rge" org an ht· reached . E nwrgt'!ll''Y admissions alltl Sur~kll] proce-dures a n.' sl"('(1<1.1 ~·tl i n g.<; d uring whic h re SpOIlW S art' frt"< plt'li lly mt' ,L'IUreti in mi nutes rat he r than hou rs. He re . delays III res pOIls(' afh'r d n lJ.: arhnmtstration arc ah no!>t al\\'a}'S lIulit'l'l1. E"t'll t holl~h plasma concen tration mon il o rili~ is un!i1w!y 10 IIC-' {'Ill plo,"l:'l l in tlwse circumstance s, it is still llllpo rtan i 10 dehn('aft' tilt' de-tenni nants u f the tune-course of res!)(IIlst.' to im p rn\'{' gen e ral IIl1de rsl alltlill~ and 10 o plim ize treatment procedures and dnl~ use. EfTN.,t Com part men t. A delay in ;l{'!Ji('\i ll~ a n 'sponse. as slllJ\\'tl by hysteresis. ca n 1)(' Illuddt'l l ;L' a de lay ill n'aeh i ll ~ an film N m IIHI11 " U' 1It or in tri ~e ri llg a numbe r of events A
nil:' 20-2:1. n ...fl. · ' (win if.It·~Ji ff,·n".'f" (m..· n":1.~ 1
fur I'l... ~.ht , 1' 1 ill .. ' '''11 1.,] 1l••1to1 " f ..n.oI".... it: pain I...f fUII(11t.. , ..f tilt· llul1tlt.lIltl 1',4 .",.. ('t .. .. ~ .. ' t l it'" of 'IOtill ·h" f l·It¥..rIy .I h~...' ..n ..i •. in 110.., .Lff' ·"'·" 1 ""'I a....aM"' " t . l l' lt· C\au'" " "1........1 1' 1.... ,,... "'" nlratit..' . B . \\1...n ..n .. If...... lUfIIl).& r1 " ,,·n' 10 U'lC."I1. ,Ilt· n ..."'h- n.-lt..:l.wi :w' h~"h'f... i. i' n·" 1. 1...'..· ....41' "' ' I. · n ·1..'....1 ttl 1I ·fT' 1 . il<· nl l'llli..n . l ..Jllim n w till. · "f "pI;,,\( fn m' I In " lor is ,ItIl,..:1 "'-:\1 I" .....-h 1.';" 1 i" I,," I, I(ml'l.. . l l>l'lI" lI f"'"1.L lll ki", I~' pn..
8
n...
•;, ....1 lor S~Tl I.·~.
u.s.."
43
5
7 6
2
I ",'.)
o
10
20
so
40
30
Unoound Naprcxen
corcentrauen. ~aIl ~
8
1.25
~8 1.00
8
I.
~ 0.75
~
~
0.50
f
025
4
3 7 6
5
2
i5
s
~
~
o --~-~--~-~ 0102030 unbound Naproxen Concentration in -ENect Compartment,· ~WL
40
C HAPIE ~
36 1
20
Ih al han · a h llll" 1'(111,1;&111 ;Lv,,,d ah·t! ,\i l h Ill" dl ·Ia~ . To Ih h l 'Ut! ;l ph;tflllat~ KlyTMlllit· 1110 KI"I l~ m l l);lr1 Il1I' 1l1 lillkt'lliu llt c' p t L,ma l~ lIIn' lL tr.l tie lll ha , "t'l'1I 11M'll . T i,t' H·I,Ililll l'l lip IM'lwl'l '1I rc"pt lll'ol' iUllll'tllln'lll ralill il ill lill' 1·ITI'C.1 e nupartuu-nt (';11I 1111 '11 1M ' lIIIKI · d C'll ;L' ill Eq. I . T h i, pnll~·t!lln · hax " t 'C '1I applil'(1 10 lJap m wll. au alla l~t ·,k . ;Il1t ipy rl'lie. und allll -illlla'tllI lah l ~' a~t ·lIl . Fi ~ll n ' :20.....:2.1:\ sho,,"s hySlt'H'sis III ti lt' nwan pain illdl' \ ill ,I tI"1I1 al pain I1 I1K ld ,L' a fllllliil JlJ o f tum- a fh' r a sing ll' .'it It )-1 IIg orul eh''ol' .,1' n,lp m \ t·ll. \ \11<'11 au I'ff, -ct (1111 '1);11'1 ,,11'111 is atlel,'ll. ti ll' n ·lati llllsh ip IM·IW('l'1l H'sp"m 'ol' ;1I 1t! (111lt't'I, lralil' I' iu til(' t·lli 'C.1 11'llIp.tt1 11lt·1l1
with an c'ili 'd
A
3
180
240
120
..-- 0-
300/
~
0
0
~
n". 2u..2 1. nIl' "....", h''''I",•." " ,,·.I,If,·.. ·"•• · \11""'1'\ ~, ...., " "' '' '' 10;0....·1" ..·'" .1." ""~ ... Fill,n ·"I",!. I \ ' F - 1,lfe l .,',..• ., fi-mW1" ,I. "f ,10"1'".1,'" '" :'If, ,~"I, I ..·" f... ", (, " ,' 1" tI... ,,,.:I, II ~ .·....... M~ a::. ' .\
0
0
~
u
· 360
~
~
05 '"
" ..,
I
2
":!:,
420
0
<;
I
E
0
I
480
0
~
0
~
~ ~
--
" 0
0
-
-
0
.)2 ,I " I- I "·J. I'I't.U
20 30
0
~ 0
0
~
u
0
C
~ 05
2
0
/ I
e ~
0
0
/ I
~
~
E ~
-"
0
0
~ ~ ~
0
0 0
120
240 Minutes
1 \ 1' >fl" " " 'I1 , \ I~:
360
11 ~"" , ., -
11'10..,"'.•" ..1.11.. "'" ... "I ,I..,· 1""f" 11 ,,,,,,,,.,, ..,,,I"'·I..,m,w1,lw·,, III f,t .· .ol,· ..1"1,1 ,,·,, e l", 1'1,... ", ... ,,,1 TI,.·•..
3 0 -
1'' ' ·''1 '11..• I",.· "I " ""I,IIlll:" 11.1,, ·..10... 1 ",'\1 '" ,·.•d ' lw.", R. T""' I. ·".r",,· ,I,IT.'r,·,• •· .." ,1,,'..1"'" " f ,..,,,. (11•• 1,..... " h •.", 1.:..11.-:-'. \ 1T . Wal" .,. I' ll E,k,'. J II C... . "
8
0
, "II.' ,I...I..~· ,1.'10:'..·••1!" "'h'W'"
.. ...lI w·I
/
10 20 PlasmaConcentration, mgll
0
60
40
c
"I..,, ,.,
11,·1"""",1,,1' 1..·' " .·.·11 ,1,,· ..·"'1..· ' '' ,,· ,Mt,·..·,....· ..,..I ,t",I"""' " 1( • • " .
90
0
c
480
CHAPTH20
36'
now shm',
lUI d l'l)('Jl( Il"lI t "l' UII lill ll"
(Fig:. 20-2.'38 ). Thh rd aliollsh ip ilia)' now he lIloc.ldt"tl
hy Ell_ I. h th.·'l)rd illion 1)( II >-",Ie n-'si.. C u rves . Ih' sl)(ll\St-' is an all-t·m hmdng: n-rm app lied to It lila)' 1)1' all 1I1l\(' l'\"alloll th ai in lt' v:mlt·s (l,l'" (·fft'(1S . it" in ti lt' t:aw o f till" uature th- d Tt't.1: of f"nJWlllitle ( F ij,t. ::!U__ I-I). Two ilio n ' t'~lI n pll"l' follow , whk-h show rhat mn- m ust lit! careful in Interpo" i ug: t'( 11I( " ' 111fill itlII -rt ' Spt JllM' (·un·t·... I n till' first examplc-, ibuprofen. a n a na lg:l'sic a m i an lip)Tl'li c ag:t' nl. is administl"rt'tl a... a rucenmn- If) :3(i «hildn-n \\il l. n-ct al n-mperunuvs. rt'po rtt't l ill l! t 'grt·"l-'S Falm-uhelt !K 'f',Vt '( ' 1I 10 2 a lltl IO·HfF (;).I).S ;l1\(1-IO..'5°C. 6 months t!lmll~1J 3 \l"i1ni) ;lIId between 10 I and II n .9"F (3.-"i.:l a nd 4ooC. 4 thmll~h II )l.'ilni ). The II W ;lII f:11I in t('Il II'll'mt u n' is noll'd i ll Fi~. 20-24A n-lsnvc to till' (1J1l(1"lltmliu n o f dm ~.l1lt' rdat iollship im p lil's t h'ltl h(' dm ~ has lutk- (·fT(>(.1 al ('arly time-s \\"1l('11 tilt' concentrunou is hi ~iJ a ndmadmal ('fT("t.1 whe-n tlu- conceutrution hax IImpp"...l to 1.5 lllWI.. ;\(1uaJly, th e ,,·IT,,"t.'! of l ilt' dmg is Rn'alt'st at earl)' tum-s ami has P;lrti lilly \\lI m lilT hy tht' ti me ti lt' h'lll l)('mt u n ' is min imal ( Fi ~. 20-2.J 1l). Temp e rat ure is all illh-gra h'l l f('sj1(mst' t hat measurt-s tilt' cumulative- ",fTt"t.·t of tilt' dm~. Usi n~ sJX'('ific Iwal tn n ·latl' km pl'ratu re dMlI~t" drMt, to uet h(,,,t trall.sfl' r. Ilu-n a \\il1,' , - arid y o f III t' ;LS1Irl'lIlt'llts. 111(' n-spmIM-' ilia)' he din -ct o r Indirect .
en
Specific
heal
'
di
Role o f heal
.. prod uction
Role of
- heal lou
E\'(' II ifllt'ilt p n ltludi()l l is ins talltl)' reduced. tim e is n-quin-d for Iltltly tellll"lt'J'dtll r'l' to fully n -flect ttlt' n-duct ion. This pln-noun-non is further d iM.·usst'll ill C ha p. 23 , Turnover Con("(' ph. for tilt' al1til1 "I~ulall t f('SllllllSl.' t(l warfarin. '111,,' hph'rt'sis in Fi~. 20-Z·M is there fore nol T\'a d ily Interpretable. Ck-arly, if tilt' data wert- to lit· ('(ll1ap....'l 1 hy tilt' 11M' of all ('fT('(1 l'()1II1li.lrt lllt' llt, tilt ' n-sults \\1Iulti ht, 1l0 IlM'IlSl.' .
1111s is lli.u1it·II],lrly so if iI corrr-lat km ht'lWI'l'1I n ~p()l IM ' aTltI (, 1T1'(1 silt , ("(II1('l' lIl m lioli wt- rrtlu-n I n ht , ;llt"'lTljllt"ll. '111t' M'(1111d exaurph- is tha i of tilt' dT{"l.1 pllltllll't'l! foll ll\\i n~ i.v. udministrutiou of {'T)1h . mpoir-tin, all autiam-mic a~t'll t W \"{'11 to pa ti{'1l1s \\i l h {' Iltl. sl a~,,' re nal d iM';L'it~. Fi~Irt' 211-2S
,,•
35
.. •
.... 1(.
r "·
. , • ,,
•
• ••
c 30
" • ,
~
/
~ ~
,. E
~
:I:
........t . ...
/
,tl
("m'II I
•
rh.. ~"!tt· .
1'....1...1;<>"
ra
;u"j •
I.......·
, h.... ~ . I;al", I' n'"d"11. ( R...[rawu rn"', U"'hlinj(" ' , I>E.. G"I It!, f .A.•
B
A
'.Il'
",>II s l..·j " .... 1. 8 .: .... pl"'m '....m it· ,,,,,. I,A ..r .·1')1hn " ....1In 11. al~
20 0
•
IUMJ,'T):"in~
R. ~:l')d'""I..it1 1" m nlln -s j.. dl;"• niMh ' p....1"<.1 i< >ll "f " l')thn M:yl"", 1I' ,"1'",r, ;trio'. w ad'ln j;: lift''1>;01'. , Lo~ '" ,.I')t hn ..) t ,1;, ' ;011 II..·
••
25
1"" "" 111
.I... ti"" .,,1.., ""·,,,,,....";1 II.............. I,,'("au,,' II..· ,It'\('I~ l,nlllo.."( ",1 "'1')110-
•f
.~
no<, h.·",. I'I<'I11 .n
,h..J:. u ;1./ ..1r'l'C'l'i>i nlt"l')d ,,,,,."1i" . ft I•• .1pi~ 11,...'1' lilll'''' " Wl'l·1o:. IIM'n"1I- ... f"r 70 cLoys ;u..1 ll"'n 1.·",ls "rr. A . ",.. dml( In............... 1'I')1I, ......, tl' pro-
•
'
2n ..2.~.
uremk-
50
100 Days
150
200
Iy. ·
fur IIn'lnK' ;a',,·mill. e li" . PI,••· 11....,, ~ . Tlw... .~I :,6-IlD. 111I1'2.)
CHAPI EP :?O
SllOWS tilt' results fro m a patient who n '("t"i\'t'(I ·IO()() unit s of t'f)thropo il'li n t1m 't" nun-s a
we-ek. T he lu-ruatocrit nws for ahollt 70 days and then levels o lT. O ne m ight he tt"mplt'(l to conclude tha i Iht, e lTl'('1 of the d m~ takes time to develop. In fact . tilt' dmg lncrvaws the mit' of production of n -d blood cells I h roll~holll the entire course of its ad mi nistration . TIlt' o!l<;t"y alillll is tlu- accuruulatiou o f lIt'w l\' fo rmed (,d is un til tlw\' have n-ached Ilu-ir lift'l ill lt" poteutml and hl'~llt() d ie . The rail'; of production and dt'ath of tl w cell s subse(1lIt' nt ly l "lllllt' intn a IIt'W sh';lIly sta ll"; tilt' IWlllatoc:rit !l OW f ll ll y l't'lIt'(1s the men-used pr oduct ion of ("(,lis indlll't"{1 by tln- d r ug.
STUDY PROBUMS (Answers 10 Stud y Problems ore in Appendix II.)
I. !mlie llt" wln-tlu-r III(' follO\\i ll~ sta te ments an " true (T) or false (F). a . Fur a dnll-t sl l(l\ d ll~ first -u n lt' r d ispusilioll kirlt't k s and pn Ml ul"illl-t a ~mtlt"{ l n "SpOIlM', tilt' duration of t"tTt'i..i Incr eases Hm-arlv ....t th dose. h. ..\ Il~'SIl'n'sis loo p ill a l't'speJllst" \"(' I"!iU; plasma dnl~ coucentrutiou cu rve is not expc cted to hc" o hS('I'\"('t1 afh-r i.v. admtntstrution (If a bo lus dose I', For a graded n'slx ltlst", th e EC!'A I is th e p lasma d nl g coucent rnnon at slt'ady stale tha t p rodmes .5()% of till" maximum rt:'sIXlIIst'. d . For n"spoTt!it"S le ss than 20% of th e maximum, tilt' response is direc tly p roportional 10 t1m~ concentration onl)' when y o f Eq. I equals one, C'. Om' shou ld wuit for d istri bution t"(luilih rium Ix"twt"t: n drug in pla.\ lt1a am ] th at at till' silt' o f aet iou to Ill;" t"stablishc"{l before atit"mpti ng to Ust" plasma mon itoring ;L~ a guidc" to lllt'mpy. 2. T he concent ration-response n-lat lons hip fo r ;1 d rug th at p roduce s a graded n 'slxlIISt" is lhmtctt' ril".('t l by un F.G.....) of 10 mgfL am i a y of 2,.5. To bt, e lTl'i..1i\"t', tilt' rt'spOl\st' tu tln- d nl l-t must 1)(' kept lx-rwccn 20 % an d 80% of t ilt' maximal value. Calculate tlnr.ll1ge uf 11J!l1'('u lmtiu llS th at art" 1I1'('((l'(l to ac hte...'e th is cbjecnve. D m g at the silt' of acti ou t"(ltlilih mlt"s rapid ly \\it1l dmg in plasm a, 3. Tlu- d.lta in Tubk - 20 -1 were obtained ill hu man s with AF ·DXII 6, a CilrtlioS(,I('i..1:in ' muscarinic agt'tlt. In p aralle-l ....-ith measun-ment of hea rt mit ', blood samples wertd r awn am ll'('ulri fuj.,'t'tl for measurement o f the plasma concentration of the d rug.
,.ltle 20-1 . 1 1. H_rt ......... PI. . . . Ce........._ ••11_1. . . 11",1. 40.•• 0-1 D._" Af·DX t t 6 -
o
o
1.00 X 10- 8
O.7ot' 1.73
10- 8 10- 8 10- 8 10- 8 10- 7 10- 7 206 X 10- 7 3.17 X 10- 7 3.08
6' 765
,.
11.6
15 8 17,8
317 xlO - 7
4 69
211
e
V~r Z""""iJ
C
~, f
_
100- dodacto< ..."",...
10- 7
,c .Paloo, o .w...... A ."""'~HF Af-OA 116, acao"""""", .. """",,,_ _ On I'toma
crb/O"""''''''''''''' "'-"'o<;odo,.nom <""", ~..""""" _
X
1.71 x 10- 0 1.00 x re-s 1.00 X 10- 4
' 47 2Q Ib 30" °Mopoodlooro~
X
7Q7 x 8 32 x Q8Q x 1,52 X I .Q8 X
40' 605
CI1AJlTU 20
a. l' n -pare a p lol of til(" Increaw in In-art ran - H'nus I{)~aritilln uf plasma d n lg concentranon. b. E ~tilllatt' Ilw approximate \·a1l1es for E-.. EC~ I> ,un.! ., lISill~ tilt' mudd
4. :\11 t':l.(lI·rin....ntal anesthetic agen t. C I...'j.fj l . pnxlllo~ ccma in human suhjt 'C1s. Table hu\\"S tilt' 1lK'",Ul dnra non of Ollila a.. a flllK'tioll u f tilt" is. (10...• uf C I...'').'U atlm in,
zu-z ..
i.'h ·n .c.J. l Do mino . E."'.. C IKxlo fT. P.. ilnll COn..WIl. G .: Pham ldc:o loWc t·fTt't.'ts of C I...>"!. a l K'\\ ' rn!>.... K;afiu· an(-sthe.1ic. in man. Cltn. Ph.mUa('Ol.l1H-'r .. 6 :2'jl}..29 1. 1965).
' . . . . 20.2. ~
IrngA gl
[).,ar,on of coma (mil'll
05
10
17
58
15 90
20 10 0
St'wr.tl ~lIhJt.'('ts. illllllt'dialdy afte r IlIt· initial o una h....1 (·lItte·d folte,....in ~ tilt· U~m w l J: do",,'. n'('t'in'tl a S('(ulUl 1 .().. Ill w\~ dose. The duration of (Uma assoda h'(l with thls Sl'('Ou(1ttel!>(' wa .. .'S.O min .."-ssulllin~ a O il(' compartment moclel. a. Ddl'nniIH' lh(· minimum (leN· of C I ~ I n"flllin'(l to pnJdu(, ' ('Ollla. b. h tht· i1K'n'a\( ' in duration of co ma ...-en \\ilh tiM' Sl"'(uml tlow n msislt' nl with lilt' infnn natioll ohtaillc'tI folk,....illg lhe.· s i n~ll' &-N.'? .'>. A compound is ~u'n a\ an i.v. hollIS to a p atient n'( luiri n~ a minimum plasma conn ·" lrdlioll uf 4(l mWl. for il t1wrd JX·ulk (·fT(",('t . Ghl'n t1",1 1>tN:' =- 1000 Ill~; k - 0 .10 I'T- I; \ ' =- ~ 1.. allli a.••.\lI ll1illJ:: a OIJ("-<,UlIljlilrtllJ("ut na xk-l, a . ClIk11Ialt· IH,....' lonl-: til(' cltnjcal dTt"(.'t Ia... ts wtth t1.i!> dUM' . h . C, llt1'lal(· I" ,....· 101l~ tln- cltmcal effect lasts fnll(,....in~ il 2(1(1()..1I1~ ,lcl'o(·. r-, Det emuue IIIl' duration of (·frt'('t foll(,....i ll~ a WII()-III ~ ,lc r.t·, if k .. lI.n ') h r - ' and tilt· t-h;III~I' ill lilt' k is a n -sult u f (I ) a rn1lfold d('(:n'.L~' in dl'" rano'; and (2) a dutlblill~ of till' vnlurm- of distrihutioll II)' inl·n ·lL\('(lllulI..,x"(.; fi(." tis ..m' hiIUL n~. d . 1)( It·s d'lIIhling Ih(' doS(" o f a d m~ ~id d the- Si Il IJ(' dlall ~c' ill duration of dinil"ill (·fT(,(1 iL.. donhl in ~ tln- half-life? 6 . ( ; uI,'ov./"j t'l ul. IIIl·a."II"'(1 tile plasma and salivu l'UII(" lIlmliullS of procainanude. an Oln liarrh)tlllllit· agem. as wd l a... Ih" pmlolll-:atioll of Iln- QT interval. an t'!('(1n ll'il.n lic~mph ;t, 1Il(·ilsu n - nf (In ll-: n -spoIlSt' . TIlt' mean data are ~i\l'n in T llhl(· 20--3. In till'S(' ..lllIli(·s, fum " .IIIIlh't:·fS n '(-'c'in "(l 511(1 m ~ o f pnll.""in'"Uitl(· h~ll n K'hlllli()(~ h)' constantmhoi.v. infllSioll ll\'C 'r 30 min . Each saliva Sll lllpl(. was ohtllilll'(l d u ri ll~ a period o f 2 to -I ruiu spa nning til(' tinu- of ''t'1I0US hl' llxl collection. TIl(' pIiL\IIl.1 and slIli" 1 conce ntrattous lish '(l an' JIl('iIllS of tilt' conceutranous of ('il(:" illdi' idual m l("tllah'( l, I" , 1lI(lllc·1 fjllill~. In ha\1' fl('l"tlm"t{ al th c' tiJll(' of til(' d("('tmt~.l.rtli()gmphic n'(,mlin~. ' a. I'lot " ''',Xllls{' \l'fSUS pla...ma pm(~.linamitl(· nlll('(·lItmtioll. h tlw rt· ('\id" I1(" of 11)...h 'n-si s ill tilt' n ·laliomh ip and . if so. is it c1o(:kv.isc· or nMllltt"n:kiC."kv.ist·? h. 1' )(11 rt"S(XlIISC' \l'fSUS saliva p nx~.li n a lllid(· C'oll(1.·ul mlioll. Is the' OhSf' l'\"dtioll simi lar to lhat in -a-? B ridl~' dis<.'I$.\. c. h Ilph-n·sb nhSf.·f\ t'tl in a plot of saliva \"f.· fSIIS pla.\llla p rot"Uinamit!c.' o)Jln'ntrdtions? COIll)'lan'llw pInt 10 thclSt' in parts -,,- and -h.~ d. R("!I)ItIllSf." \'f.'nus t'tmt'1.'nlr.lt ioll plot s Ibat she,....· "~"lih-n'Sili an' soml'timt'S modck'tl \\idl an - t' fTl'C1 oompa.rt llJ("lIl.- Brit'fly npl;tin wll~' Ihis appnlil(:h may ht' u-w ful.
CI1APTEIl2Q
36'
..,1.20-3.
T• M __ PI. . . . ." . .II. . ce_........ _.1HI PNI.~_"QT 1 - . - .1&*-I""'al_ .. 500 . . tIyII......Ieri... Ov_ 30
""".1_.1,,,
I. I_It" ,_, V.I.........
"" , .....
0 8
CCf<£N1iJ.f'(;::N
CCNQN1iJ.fO.J
'""'" 0
"'" 0
30 42 4I
52
237 1 88 1,5A 1,35
127
1 20 1.06
33 44
70 97 157 194 257 370
l'9OIQNG.J.f'(;::N Of 0 1NTl:....""
19 3.5 6.7 87 70 56 4I 34 30 26 22
23
12 23
-
".""
""""
w.r..on AJw So:>< <J
. 1.
0 .92 07 A 0 50
0 37 15 7 176
203
16,9 160 123 12,9 11,3 11,2
72 83 03
17 3 104
r, T ahlt' 2(~ lists tilt' d uration of dTt'ct achi."\'('(t with till' neuromuscular hlodcing agl'nt pancurouium fnllo'ling thr- administration o f it 0.0"2 mglkg i.v. dose each time the rt' S! )(Ill '>t' ret urned to 10% of maximal t'fTt'<.1 . Assu me that dm~ at the site of ucnou
rapidly eq udibrates with dru g in plasma.
,.It•• 20-4. OOSI'
N••,.••ac.i., .1_11.1•• I,,"," s.cc.HI.,.. DelMa-" h ac..... I• •
1\l.IWlf: ~
Durcr>on 01
14
Ellecr (mmt ~ood\oooo~ ~, ~C ond~, "
Z
3
20
36
~
>54
~ ~ 1Jo.oo-.• rZ7l4-7~ Z.'97t Or'9"""JI dao::l""""~.J . Tho~I:b:u.g<xlO'ld~ .. "U'do.onng~ Ilo-l ~ .4 VW-J l 0. 1970
.. (.;.l;",o;.M .l-r.G ,ondw--..l>.H
~OZ"'9-"~"
"'_0>_o-9O:l<J"""",","",_
it.
SII!!J!;t'st why the duration of e fTl'<.1 p~ressi~·t>ly Increases each lillie a dose is ad-
mmisn-n-d. h. Will the duration of e ffect cou ttnue to increase if drug admintstration cont iuues to lx- admhnsten-d in the same malllwr? k . ~ Ic Dt"\i tt , I) .G .. and Shan d . D .G .: (Plasma ccucentrations am i the time-course of beta blockade due to propranolol. Clin. Pharm acol. Th e r.. 18:708-i I5. 19i 5) observed a linear relation ship be -tween efTN1 (perce nt reduction in exercise tachycardta] an d tlU' I~a ri th m of plasm a conceutraticu of propranolol. 111e slope of the Iille \\'3S 11.5%. Tah lt· 2(hS Iht s tilt' t'!TN1 'lith tune after t .v·. udmtuistrunon of 20 109 propranolol.
,
lINE (!wI
Peceer 'ed\IChon 'II e~efc j~
IOC hyca,d lO
28
255
22
, 15
8
Estimate the appa rent hal f.lift· of p rop ranolo l in plasma. h , Citk ulatt' how l un~ tlw n '(!ll<.1ion in exe rcise hK.'hyc-.mlia is t,xpt'<.1t"tl to remain ahm't' 1511 (I ) afh' r a 40-m g i.v. dose and (2) after a 6O-mg i.v. dosc .
it,
CHAPIU 20
9 . Pn-dict till' ~I 'Ill'ral h-lld('IWit·s (d od . . .vise, counterclockwise or 110 hyst t'rt's is) fo r tilt' oIN'rn- m~ ~\'t' ll in coutrolh-d-n-h-ase
METABOLITE KINETICS
OBJlCTlVI5 The reode! will be able 10: 1 Slale the phormocokinehc parameters rho! influence plasma melobolitecceceenouoo and
01 merabo/'\e in the body loIlo-Ning drug odmir\lsrroliOn. 2. Delet'mioe jf elimination ol 0 melobo/ite is fol&timi!ed by il$ lonnation. 3. De\e(mine if 10101 clearance 01 a mek:lboIite is Ies.s thon tho! of il$ porent drug, given plasma ccocenncnoo-nrre dote fOf both drug and metabolite following i .v. drug odminiMrotion. 4 Describe the consequence 01 hepatic eJdrocliOn on plasma merobolile concentrations 10/0 Iow-ing oct odministrolion 01 0 drug 5 Slate the phormoco'.ine!iC: parameters thol coorrol the cceceoectce 01 metobo/iteot pIoleaU followIng oominisll'oliOn of drug as eirhef 0 conslonl'fO/e i.v . infusion Of a mulhple-dose o mounl
reg imen ,
why efiminatoon holf.life 01 melobolite is the delerminonl ofcccccl 01 metabolite. when a ccesont amount of drug is maintained in the body. 7 . Describe why e!imiooliOn half.lifeol the slowest step, drug elimination, Of melobo!itee1iminotion conlroo accrual 01 melobolile loI1owing drug odministratiOn ei/hef by conrontfole 6.
Descr ibe
drug infusion Of as 0 multiple-dose regimen.
8. Cokulate the OV'eIoge ploloou concentrohon of me/Obolile lolbMng on oral multi~ drug legimen, given the dosing inleM:ll and the AUC of the metobolile aftel a single dose of the drug 9 E"pIoin why the holl·life of a dlug, which i~ ,enolfy exceed unchanged 10 onlya ynoR exter'll and undergoes intercortvel~ion wilh a metabolire, con rocecse wlOnlially in pclienl~
with renol function impairment.
10, Cclcoce the apparent fraction of drugcceeoed to a metabolite u~ing AOC mea:w,emenls ofdrug and metabolite after sepcrote doses of each.
'I'll" n';". III Ii Ir uu r inn-n-et ,ifill {'(JI I{'('n1 \Ii lh m{ 't;lI Mllih '~ {"a n hc' .~1 1 m m l" I II Jl ill (illir wCln k 'I(·tic l1I. It,\i, 'it ~ , ililliliiticul. ancl d i'pla('('m"lIt , .-\ 11 tCM llllil' n Illt'tal Mllih 's an ' 1'"u I ~I.t Ilf a ~ wl'a kly adi\ I' or illadin ' wa~ h' pn MIIl(·h . Fo r mall )' this b <;1"1. hilt ,l~ "'i'll in Tahlt' 21 -1 for Illall.' ·., tl!t·r, it i' IH,I. SI)lJu,tillU " lh t, ae;l'nt ad mini''''n,,1 b a n hu-rt p n Mlnl e;. wl.k h c l c'pc' l lI l~ on 1l11 'laI M,Ii'1ll lilr adh a lio l1 . E \a1l1p l,'s an' r-naluprtl. \l'llid l is h~ c1rlll~-/c 'i l to t'nalaprilat. an a(·th t' ;llIt;o h'n'iu ·('(m't'rt iue; " 111.)'11 1<' L\ C El mhrlutor. a mi prall'jl;\m , w llidl is lI11'tal>oli"..1 to tlu - adh'c' 1"" llzlM li,w'pilll' t1t"Ill"t llyldi,w·palIl . SmUt' nlt'l al""lih's h"n ' ph.mua('(,llle;i(' I' mpt 'rt i\ ' ~ ill rouuuou \Ii th III(' ,"'trt'nt d Ole; ami au \.(ull'nl ils ('Ill",t. SOUit' lI1\'t;\I>o litt" II;ln ' a di lli 'n 'lIl pl.aml,udllt;1' profih- alll lmay P H 'II 1M' lilt' 1';I1 l'(' of tmi(·ily. ( Jl IIt' T rlld "IH 11 il< " a n- ill.11'! hI' hill llIa~ . h~ ;1(·till\.( ,l' inhibitors , pmlolll.( o r \'1\11;111('( ' IIII' rps po llsp 367
CHAPT"Ei121
CCWK.ll.N:>
~m't D
.\.r''',1'>O r,'
·.\f:Aj
;1~1
'11.1"",.1<
bocco.oe
,.
'v'".p<:,.~ ' w'
."""'o!ph,r""
Ca'tJ('-'(l.',..P .....
C':>'
~TH'l:D
1'>0'00<(, {lo.' 'l'n hOI(>
(l(,(J
;.- ;Xl'" 1'.'
Ar"
C~
P""ro , ..,1
"".,·r"
'0£'
p,(u- rnm
-~i
P,cdn
ell '1"'-""">0.',,,,,,
P,-~
!.OI ....
Procu '\<..I"",j,.
0<*0(:
D v,:,r~;'T 01' a,''
P'ol"()'doi Q"n'd ''''''
E'
VerO I:oQ'T
floo "·',,,,,
ZIo(l(MJ(l,'",
Sul.~
h I~Qf."r,'
to
SINGLE DOSI OF DRUG Rate--Umiting Step T n app n -ciah- tilt' fact ors i ll fl llt'l l d n~ lilt" ,1I1l11unt of lIll'tal l(,lilc- in tlutilllt' f()I1 Il\\i ll~ a si ll~1 1' i.v. duS(' Ilf drug, conslder till' w llt'lIw:
Me tabolism A Drug in
Body
Metabolite Elimination. l im}
1 I( MI~" A (m ),
\\i tll
,.9
MfTAKlUH KINE TICS
CHAPTH '}I
in which dnl~ is (111\\'t,rt l'll to a ml'tabolitl' that, ill turn , is eltnunated , 111t' two sh'ps art' d lanK-ll'ri 7'('l 1 by Ill(' fl'Spt'(ih't· Hrst-onh-r ran- constan ts kl aml k(m ). 111t' 1J\'('mll t'limi nation rate e ursta ut u f ( I m~ ( R) is tilt' slim of k,aml k,,,,,,,,,.l hl' mit' constant for ul lll'f routes of dm~ l'Iiminal ioll . Also. at any ttnw
kf • A Role of formotion
Rate of cha nge of omount of metabol ite in body
l(ml -A(ml Rate of eliminatio n
Slridly sl'M'aki ll~ k, ' A r efi-rs 10 r un- (If (' nil)' uf ult'taholitl' inlo till' systl'lIlie eirculatton. It nlllY nol I II' its r ate u f Ioruuuum . SUllw lilll('S, a Ilwl"ho!ill' fonned withlu ;U\ 1l~,Ul is further Illl' laho !i7'(11wh ile th ere, !"l that onlv il fm(i inn of Iht' fonm-d metabohn- is fel(',N'l 1 From tin' o~all into IIII' hlollllstn'am . l 1lis' is refern-d to lLS ,w'f/,w rltln/ mrlnboliwl t111rill~ p"L...sa.~e I hl'tltl~h a n organ . A llll'tallll!ile fonm...1\\i thin till' [ive-r may also II(' I'X(·rt·h'll into the fl"(...t~ ' ;a the hill'. FOf Silllp lidly. in tltl' SUhM'lIIlI'llt discussion. o nly the case in whk-h all o f till' Illl' taho !ih ' f(lOlIl'l1 n-aches lilt' svste-nuc circulation is 1.'tlllsid t' rt'(l. In tlu- scheme lIhll\ '(', ('illll'r sll'p ran '1)(" mlt' -Iilll ilin ~; till' rute-lmunng slt' p h,L~ the smaller rail' constant. Fi,gtlrt' 21-1 . two '\{·milo~arilhlllit., plots (If tlt e amou nts o f t1n l ~ anti Illl'lalMllih' ill lilt' 1MIlly a~ai nsl time- fullo'\;I1 ~
A
100
"i 0 0
Metabolite
0
0
, ,,
"0
Metabolite
,
C
--
0
0
B k > k(ml
~ ~
10
C E
- 10
Drug
"0
...'"
100
k < k(m l
1
'" < 0
0
E
0 _1 +--~-~-~-~
o
3
6
9
12
0.1 +---,..l-~--~_ 12 o 3 9
Hou rs .1". 2 1_ 1. C.. m' ~ I' ''''TK~''S "r a n. h· lnnil alit.., SIl''''l1 in ",,·mit."I:"'rillllllk · plots uf dn,~ ....d '1M'T"h" tilt· , .-\. \\l "'n 11..· ,-l im inal k nth' mmt.... 1 of II... tIn,jt is .. n;o!lt- r Ih"" Ih.., ,,( IIwlahol ilc·. n......tdil l' (t-Illll n "li .....,IIt~I Ii , ..·) ,I."C."i. - in 1' II.·1 ...1Ih IIIf' "n,~. H. 011"""'"1:-'. ...t ... II..• t'limin.
n
"I'
1,, - 1. .. 'SI".....i' ""I:-· ill II",· I..u,·, .
I"·, tI"",
370
f./iTA8QUTE
' 1m) . Aim) Elimination ro le of metabolite
-
fTC
CI'W'TH 21
2
For mation ro te
of metabolite
(..!5L). Amount 01drug
Amountof metabolite ... in body klml
3
in body
( 'LSI' , ,Itt' Ilwt"ho!itt· declim-s with til(' sann- half-lift· as ,Il(' dm ~ . :\ metabohn- accrue-s snh stau tiallv ill t!lt· hod" 0111" when its ('!illlinatioll is the slow(·1' Slt 'p . That is. til(' Imlf-1ift· of 1IJ('lal xlhtt· is IOIl!?:t· r' thai; that o f til(' 11m )!:. \\ 'hen this (K,(11f'S. d n lg is Illos tly I'lillli na h '1! hy lhl' tiun- till' md aho litt-I)('ilk is n-ached: dcclhu- of lIll't aholill' is tlu-n (1Illtm lll't l hy its l,lim inat ioll " air-li ft', III E l l S. I III 3. k (lII ) n-fers 10 the ra il' cons tant for Illdaho litt· ehmiuutkru. Jmt " ow lIl il lly path ways an' involve-d ill lllt'taIMllif( ' t'! imi! l
In th is
C
.~
A
.>"
B
,
"
,> E
-
"
F
G
-
ow
H
-
"
-
"
J
0 in whi(·I1 .-\ n Oft·" In till' d nl~. C 1 1 1R1lI~h 1 f(·ft' r to Illt'tahol ilt·s. J is tilt' . '-'u·f(·ftod Illt'taholit l' 1. und tlu- number ahoH' (·ad . arrow is th t' value o f til(' respecnw rute constant in hr - I . (). \\1.at is II\(' rah· .limi t in~ stt·p in III(' entire s(·l l lJt· llt'(."~ A . Elimination o f nu-taboltte G, t l 12 0.69.1,10 .05 13 .9 hr.
=
=
Q . \ \1 1at are tl ll·lmlf·!ivt·s for dt'('ay of A , D , E. 1/. and I Imm ti lt' 111)(1)" foll o\\i n~ adnnnistrution o f d m~? A. Di sl lt ,~iti()11 o f .-\ ratehnuts dl'(.,lim· o f lJ am i E. t va = O.69.1I(O.C l1 + 0.2 + 0.3 ) '" 1.31 l rr for A , D . and E. E lilllillalioll of G rate-limits terminal d('(,Hm' of 1/ and 1, t ll'.!: ". 13.9 hr. Ot '(1Islollally. till'
hal f·l i \"{·~
of d nl g illlIl 1I11'tallt,lite are cotuparuble, and then Ileit lll'r
~ tt·p is mt (·- lilllitin ~. 1I0w(...-i-r, metal MJlik dt '(:lim's IIIOrt· slowly th an anlidpoth '(l Innn its hillf·lift· akuu- lx-cause SO/lit' dnl ~ remains to sustain tl)(' 11...·(·1o f 1I11'tal MJlitt· fo r 11I11(:1. of
its (·Iim inalic)ll.
Plasma Concentration Tla- pn '('t'(li ll ~ di M.·llssiun . Iwlpful ill n 'a lii'ing tilt" im po rta nce of rah· · lim iting ~ h·ps. dt 'als \\it h amou nts o f IImg alltl lllt'ta IMJlilt· in tilt' Iltl(ly. 1I0w('"\"(' r, plasma coucen trutions a re 1I11',L'> u n'( l ami an' of Kft'llh 'r Interest . F urthe-rm o re, ill most (:4""OS. a uwtalMllitt· hilS llot bceu d l' ,m '(l for hum an use- hy n~u latOl)" allt horiti('s to perm it ck-n-n uination of its \,,11111l1' o f di ~trihuti llll
MfTAflC)lJfE I:....ETlCS
CHAP1H 2 1
371
tlt'III'111d rapitl input o f tllis .~ It' mi d. One solutio n I.
Role 01cha nge o f om oun t 01 melo bolite in
C~
=
.C
CLlm} · q ml
body Rate 01
Role of
melobolile
melobolile
format ion
elimination
wln-n- C l../ is ti lt' d t·ar.l.l1l" '1\<;(Jl'ialt't! \\i th Iht, hytlmlys is of tht' 1lt"lIlislll"(;na!t' (",IN to IIwthylp rt't lui<;(IIOlll', SmUt·tiUlI's n -fe rn-d tu
AUC{m)
AUC
_..3t..
5
Cilm)
wlll.'rt' ACC( m ) mn ] A l 'C ' In' tilt· total an-as under Iht' 1Ilt'lalxllitt' a nd d Ol ~ t'Hlll"('ntnllillll'
10
.oIK. 2 1_2.
l>i-pt.~ . ..1 " ·"' ilo"l:"rillo.
"'i<...I1~· ....· II..· pi "f tlJ.11,~ tl'"..lni.t1l
",,,, n"""'I.",I;' '' I' , lel "" ..I iii Wil· 1,·r·"" I"hl,· I"·mi.." ..';n ,,,.. • "sh' r (0) r"IIe"';"1: ,m i,\·. I.. ~, .. ;n;', 1;'..1 ur 0,11 '''I: "f II..· ..,.I,·r; ....,..'S ,,f II .,,1>;'''1' . T1... ,I,"(·lin.· " f lt l<' t "~ Il'rN ln;,,,lu1I<' It ..,, - 2.': 1Ir) i . r"h.. Ii",;"..II~' ili .li, . p".i1;'lIl. tI.>! I ~' tI.., 01;'1'' ''''1;''' 1 ur iii I..·",;" ; n",'" ." I<·r (' 1/1 - n , 2.~ I.r). n... ( · M ul mdl,~tl'n . lni .. oIc"... i. Ie,...·! t1 n Ii ....1 " I iii 1o,·mi" K'(;""'lt'.
....
'" (..."oJ".."" ,ll1lwTl f""" II..· ,~ ""'." I;'", (",..' n
. " , .. ",,", ,,,,,,,.. 1;"1:
. h,,, .
pI" t) 11...1 II.., ..K e "r "..11,~il' lui. .. 010 _ · is II... la"""r ,,f tl..· "' I K," ,Iuwn rrom D....·",lur r. II., \ 1,, 110 u....m. II .. K"I..Ie'\\'IlnI. I'.. 1I.·h. le·r. J, "" ..I S.:I,mi< lt. E.W.; Ki,.. 1i<...
0.1
o
~ 1 1>n ..I"i.. oIo"..,
2
4 Hours
6
8
ur mdl,·
.uKI ih I..."';.,K"
....I'·
,·,It·r, Clin, 111afl"....~ . n "·r.. J;-,.'it ~2 .~ r.. I Y-'I.~.)
ME1ABOlJlf KINETICS
3 72
CHAPTH2 1
till\(" profik-s. rt·slx "(.1:iwly. Sllh stit ll t ill~fm . Cl. for C' 1' wlwft'fm is the fml:tioll of an i.v. dnS(' o f dnl~ ('011\1'111'(110 systt'lllk a lly
AlIClmJ _ fm • Clearcoce of drug Clee re eee of meta bolile AlIC
6
Ih ·t.. m i n ~ III Fi~ . 2 1- 2, th e' data SIIAAt'sl that th l" an-a fur met hylprednisolone (A UC(m) is ~rt'ah' r than that for tilt' adruini sn-n-d ester (A VG). Calculation co nfirms this; the re"pc'd i\'(' a n'il-S an' 3 .9 am i 2 . 1 Illg-hr/L. Al1:'(m IiIlKly. sinn .' th e value of 1m cannot (·)('('("(1 unity. tilt' ck-arunce of lIlt' th ylp rt'i.lnistJIIlIll' must 1)(· les .. than that of its es ter. If the rat ln o f areas Imll h('('11 It·ss than I. then. 1I111(·ss the value o f fm is kmM11. tilt" n-lative total dc'ar.lIll't' "" IIIl's cannot lit., a.s sessed. Because no kllowlt'd~(· o f lilt' amount of (! m~ ill Iht· hCltl~' is Ilt'{'('s sary to um w at lilt' ahoV{' conclusion. thi s an-a !Ilt·thud of i lltl'rprt-'tin~ meta ho lih' didil can \)(' t' xln ' nlt'ly IIst·flll. t'sl)(,{1ally in cases uf dnt~ poi solli nJt ill which Iht' amoun ts i n~t'stt-d alii ! absorbed an ' fn 't jllt'lltly unknown 111t' Sl.'{"lJlld example- deals wilh propruuolol. Hil-'il"tl on tlu,.o dala in Fi~. 21--3. obtained aftN ~hi ll~ propranolol illtnt\' ·lIollsly. tilt' d nt~ has rln- followin~ cha r act e ri..til's : tot al dearuucv, 1. 1 L'mln: volume of t1istrihutioll. 3,<)(1 L: ami e limiuunon half-lift' . .. hr . Other data S ll~t'st Ihat almost tilt' enure dost, is mt'labo li7.("t1 in tilt" live r. ~ ft't ahnli h's of pro pranolol ;ndll( lt , Ollt' o r mon- ~1 1I<' ln lll i dt,,, ami napht hoxylat1ic add, which was measured "1)('{, 6(,'a ny ill this study. \\1lat m il 1)(' learnrd frum lilt' data dL"p!;t}l"tl ~ Ill i l()~a ri l h m iedlly in Fi ~urt'
21--3?
From (,'1I11Sidt'ratiolls o f areas o f dnt~ am i metabolite. one 111ll.s1 ('' l llld ud(· tlmi tilt' cle-ar,iIl("l' of naph lhm:ylal1il' add is 1IlU('1. lelw('( than th ai o f propranolol. lt oWt...·N . lilt' p arallel t1t'{'it\, of ml'laholih ' and dnt~ im lit-.tlt,s that elimination o f thi.. lIlt'taholitt· is rate-hunted hy it:s fo rmation. lI t'II(," , the- elinunariou Imlf· lift' of this ilion' po lar nll'laholile must ht' s!.nrt Pr. am i tilt' amo unl in the- hod~' a\\m~'S low er. than Ihat of the parenl drug ( St'C Fi~. :21 -I Al. 111t' o nly (·\planat io n ("lJJlsish·llt wtth th ese observations is that volunn- of tlislrihuti oll o f llIt'1alM,litt·, \'(m ), must 1M: smaller th an that o f pan'nl drug by a fact o r ("-1.' 11 Wt·att'l' tlmn
t 'il(. 2 1_1. s. ·"' ile 'K".uillulIit' l'lot uf th.· r1.l-'tnlt .~ ..w.~·"' r.llio,,, or p" 'I'm".... oI lO) ..,,,I uf "I,,· " f its 111.....1...1110' . " ..p1,tI..>~~t..1ic·IK-;'; I I ., .~,I..r ). (me'''11 :!: SE M) Itf' ..r It '; 1ll:1o. h . •Ie....• ur 3.7 llll: pn'l, r oI"l ,u thr...· , ,,bjo'l1', ~ "t<' ,1...1 tl.., ,·Ie" -al...111...1..1.. ,.lit<· \.........·" t m' i< ... ' .Io'l·hue.. in 1 11..1"'ith 1,..,...111 ,Iru !( 1,,'(,..01.. •.. f It Io",..'r ' 01.1 d . ,...· " ,...~. a,,,1" "nalle·, \1,lu",. · .. r 1}t..1ic.- ..del t"lIl1"'n~ l ...i'I. I'ro , prd,,,,le ol. Fur a ,Hid t" "'I>an'''''. tI,,· "al' htl......~t...1ic.· lKiel .J'"UItl he' '''1,"",-"..1 in pn'l".t'''.lc.l ' ''' '' I\;olo·nlo. hUI tI" , ,liff.'rr'" ..· in th.';r ",u""l'\,lar "'''';1:1,,, lZ6l1",,,I 2Il4. " "IM'(1''''~' ) ; ' ' '''all U "'WI, uf pn'lmu".teol - 3.Y ).1\1 ). (R' '1Ir..w" (n,m Will..•. T.. Ce",r...li, EC.. Walle·. t.:.. Fi\J:"" . T.e .. and (:..fT"" ,. T. E., ~ ..1" 't1.....}t..1it:· ",."Iafhor ,i,,~Ie· ;ul< I Ic"' J:-t<'n n el.-..... of Im 'lm'I " ,le ol. Chn. 11,.tn"",~ .l . n M·r.. 21);S4'h'\.~ . HI7il, 11' 1'" ..1",~ ..1with p" nni"i<"1 "f (;.\ '. \1 " ", ,:\,,)
100 50
is ~ 10
~c
<3
5
5
a:
o
5 10 Hours
CHAPTH 2 1
M.ETABOUTE I<J'.lETll:::S
373
til(' ratio (lr t'!('arrlllt'· values. l1ds conclusion follows from a comparison or tilt" elim ination rat e con stan ts fe r metabolit e and drug:
11m} ClIm}/ CL - 1- ' I1m}/ V
7
For k (m )/k In ht· v:n'aIN than 1. the ratio \'(111 )1\' must be smal ler than CUm )/C1~ . COIl ' firll\in~ this {'u ud usioll is a concentration o f un-tabolit e m uch blghcr than thai of tilt' parent drug ( F i ~. 21.....'] ). despite a much IOW N amou nt or ml't alKJlitl' in the hody \\11(:'11 elimination o r lIlt'taIKllilt· is form ation rate-linnted (Fig. 2 1- IA1. TIlt' fiu dtngs with propranolol anquite {"{IIlIII1(mly eucouutered . part icularly \\ith IliL~ic d rugs that an' conve rted to acidic IIwtaholih·s. ' n i t' volumes o r distri bution or these ba sic {(n lgs art' ortl' lI in e xcess or 100 I... whereas those u r the-ir addi{' metabolite-s art" do'St'r to 10 to 20 L. These - metabolite-s not ouly an- ilion' polar ami tend to hind les s to tis.~lI(· constituents than the p aren t d rug hut ulso an' bound mort' sln lll}?;ly to albu min. thereby further res trtctmg their d istribution . Kint'l im lty. ghillg an i.v. bolus or d m " and measuring the plasma me tabolite conce-ntrunon is similar to ~hi n~ an oral doS(' of dr ug and measuriug its p laslll" concentra tion. III IXlth situat ions. Iht' aplx'ar.IIl('(' llllli disappearance or a species [metabolite in Ollt~ t ·
11m} A(m)
A
I
Eli mino tio n o f me ta bolite
Meloboli! m
Drug in
Metabol ite in body
body
I
10 Ao
A
Etiminalion of drug
Ab sorp tion Drug 01 a bsorption
0,"9
site
body
ln
Hecall from C hap. 4 (Extrava scula r Dose) that tlw peak plasmu concentrunou of a drug t'x1 r.1\1l\t.'u larl)' reflt'<.1s tht' halallt't-· 1)(·I\\·t"l.·1I r ates or d r ug absorption a ut! elimination. Conv ... p<)ndi n ~ly. tln- 1..5 102 hr req uin-d for nap hthoxyla<.1 ic add to f('adl i/o pe-ek ill Fig. 2 1--3 reflect s til(' 1",laun ' 111'1-.. \1'('11 rat es o r Ion natton and elimination of this metabolite. Tlu- lust examph- t,,{lIIt" n\S tolbutamide, an effective oral h)1lOl?;I)'{,·rnit· agt·nl. lliis t1 mg is (·.\tell siH·ly llI(·talxlli".("tl to hyd nJ~10Ihutm llide. which . although active , is the rap('lltiC'dll)' unim portant . As seen in Fig. 2 1-1 . the concentrations of 1J)'d roX)1olbllt amidl' art' so low thaI they never augment II\(' (·fT('(.1 or tolbutamide. On e possible e xplanation for the low coucenr ranou or md alxllih' is that litt le is formed. H owev er, ill tile case or tolbutamide, IlilS{"t1on uri na ry n'(.'{)\·t'I}, almost all the d m g is converted to hyd mX)1olhu tam ide . 111at is. is d oS(' to I . At"t-·o nl illgly. tln- 200 -rold mtio or drug ami meta bolite areas f(·f1 t'(.1:s a t"{IfT('sj)(md ing ratio in total clearance \11Im'S. wtt h that or hyd roX)1:olblltamidt' Ill'ing the IlIlIdl hi~llt'r or tlJ(' 1\\'0 . ~iH'1l
I".
ME TAflOlfrE KJNETICS
374
CHAYTH 2 1
100
. '111:' 2 1-4. ..\ . "hj",.1 n-e.~,w~ Ii I-RLv. I.>lus .. f ..,,1."I''' ''it lo-, n M' (U ll't·" tr ;l./ i"" of lu lh" t.. ", it L.· ill pLI.\lllil f;o./l. "ith a I.alf·lif., " f 4 h..\ ltl....'ll;h uu Llliu.. '" l,u lr"~\1. "IMI' al1\it "· i. ;d,,,...., ..I,lilo:;dnrY fur ,,"hnl;'''it!t-",·li'''illli tk'''. II... 1'La." "li .'tIlK't·" trolliu" ,,(
Tolbutamide
,I,i. II.. 1... ...il .. i. ;J...1I~' ,,'':\"' " M ', ' '''' 'inl{ In ih t"' -
.,
I"''''' '~' hi!4J d....nonn ·. A' 1i '''''''' ''Il'lIn'', '
••iI' ..,lam· ill.· ,·lirninatiClII . (T'''''"t..m itlo.·: I 3 .7 fol ~l; 1I~t1 n ....~1"11>" l a "'id,.: I rnJ(l1. - 3..5 1I ~ 1.l (H•• I"""..
",I:tt. ,;.
~drOxytOlbutamide
("mil \ I.lin. S H.. a'll l K<.....ia..d . \ 1.: l). 1,'n ll i" "h" "
Hf ,,,n,nl""'lcl.· a'M I "..1al,,>I, I,", in hl"luj;(it·..1fl"icL. , ",,;0/. 1. 1.. ·n.Ii :M>.'i--II7fi. lyj3.1~· (• •Il r1.~' "f \ '.trn·1 1),·H.•·r. b.....)
0.1
o
20
10
30
Hours
Impact of H'patk Extraction IIl~t'sl i n~ d m K" Ihat an - (']l',Irt"t1 bytln- hvr-r is Iilw l akill~ a mixt ure of dm~ and lIll'taho litt·. 111t' n -ason. it" Illt'utimlt'tl in C ha p . 2. is tha i all ill ~" sft"tl d rll ~ lIlust p.L"S thnlul.:h tilt' lin'r I",·fort, t' lIlt'ri ll~ tilt' ~t' l lt' ral circulation. 111t' t'o lllpc",itillu IIf till' mhhln ' ]t'a\i n~ til" liwr dt ·I'lt.·l\(ls 1111 1111' 11I'patk extrac t ion ratio u f tilt' d m~. \\111'11 Iltt' t'xl rad ion rat in is hi~h . Illl't
A;p<~
'.., pror'1I<Je
Air·
1!>O'>OIn.de d n,lral'"
I'
ply"'''
Bu5P '00<"
,~rj"",
Cod<,o,r....
'\'0'1'00<00
Des rscmoc
O"••,'opr~<\I~
,\~,p',
r."
rcoo-o-e
0' ,dr("-~golOm oc 0:'0':e ,..,
Perlo ' ;1 "".
Do,,,p·n Eoco-n 0.,
(;>, n
Prop<"~ d~ ..
V",r<J(Xl'"
t
C HAPTH 2 1
tration of pr opranolol. Compan-d to the situation follu\\ing an i.v, dose (M'(' fi !?:. 21-3), the naphtlloxylad: it' ;u... ld-to-propranolcl ccncent rauon ratio is m uch h iglw r. am i th e meta bohte l'lIln'ut mfiu ll peaks ;1.~ I.·a rly ;1.<; the pa IT'lIt d m ~. TI ll'S(' observations an' understood by t'xa lll i ll i ll~ th e f(Jllo\\ill~ scheme:
Gastrointestinal
Body
"~t
Drog Drug
-----i<::: liver
-
-
•
J •
Meta bol ite - -+
As alliidpah'<.! fm m its high lwpatit' clearance and con fi r med hy l11mpa ring AVG values after oral and i.v. admtmstratton wtt h co rn-ction for di fTt·n ·lIl't·s in dose, onlv 2 1% of an oml du st' o f propranolol filters I);L~t thl' liver; till' majortty enters lhl' !-xxi}' directly ,LS Illt'taholih·s. TIll' smOlII fraction of propranolol ah sorbed !o)-stl'm il'alty is th en handlcdhkc all is. dose of tilt' dmg. Thus. till.' OhSl·I'\·t'<.l (1)1ll't·ntralion of ea ch lIIetabolite is till' slim of tht· amou nts dl.·ri\'t'<.! from tilt' two MIUrl"l' S (F ig. 21--6). TIlt' tlu-rapeutn- illlplil'iltiolls o f lilt' pn'('t'<.!ing di st'llssioll dt'I)('1I(1 on till'
100 50
rt.
~ 0
.:; c
.2
;;; 10
'"
.trw.
~
0
c
0 U
Fl!it. 2 1~. ~'",i~ ~arill"ni<' 11~J( "r Ih. , rlll-' llla 1.~ .. " ... "II'I1 10 Ii ' 111,;...1, . lu ;I, ('OI ' I'''~I('('' "r ..rt ,·n, i... 1"1"d ir ""1 ah.>I" "" '"'~''' , ,,,..:II f 1i"rI"...1inl..d . nM' n·IIIiU ,..I.r-r al'l" '" '' , " " "I,,>lil<.,;. so.. -I, ...~ JI..p1'lt.. ,,~-la.1 i<· ;o(id. "tlktl n·....-I, .. 1".,,1< ,...I'M' ..I II,,· ...." Ii" , 1'"'Im..." I,,1. l.5t.. 2·1,. ..fiN ,Imlit I",inht n.llio". t'''r .. o.1 "''''I",n.. ''I . tI,,· ""I>!,tI"n:ot.o.1K- ;Kitl oh<..,IlII 11· 0'\1'0"' 1in I'm!' ...." ...>1 '''I',i\ < ;1,1.." IJU l tI,,· ,lifT,·...'....• in II,..;. " .."'....,L.. ''''iW'h (2fi(1 ..,,, I 2'>4 !i""'!<'. 0 ' ' 1""'1i ~· ) is ,,,,all ( I "'WI. ..r l'"op."I..,l< >I - .1.9 ~~I J. ( Ht-.;I. ""T\ fmm Wa[I.r. T.. C"".d,!i. E,G . Walle'. K. t'i\lt'.IJl. T G , llrKl ( ;;olT,,,"". TK : Xajll'II,,~I;oo.1 k ad.1 ,inJ.:"· an,1 l<..,Iit·I, ·n" ,l<.....,. "f P"'tmllK,l<>I eli" . l'h.orm;.n >l. Th·r., 21i :~"_";''H . 1!J79 H 'l'" "I' K~ ..1";11. I" 'mli"iu" "r e x M , ,,t ~-.)
5
~
E
~
if.
0 5 10 15 Hours
CH....n u2 1
3 7.
. "1" . 21-6.
FOIIIc..., ,,,, an ,......1 & .... uf .101,,,- tI...
.. h"·f\·l~l pL••",,, coece- ntr auon o f ", .. l..ho ll,,· 1--1 10 tI", " m , ..11l,,-t;d••I.I.. ("'m ...... . .... , n.~ ...' lhoo. f" nn...1 ,I",; nl( lho' ,,1"" "P'MIIl of anll/: (••• ) .,,,1,10., f"nn ...1fn,m "I"".,,"•..J tin,,, (---l. :""1...
100
~
.3
Oil
thi. ,,·milc'f(..ritlm,io; p'ut . !I". ,L..1 i lM' .,f ,,"". l ;a}. ~ ' l.· f" n"....1 tl uri n " al""'>rpti..., i• •1o ·m ' i 1
,." i;
,,~.
U
,10.. ,-limin..lin" h..lf.hr.- of th.. ", "hohl . Io........i n...tal.,li"· f,>n'M,J (mm tI,,· Ill>· ....10 1 elm/{ i, ,1e1,·m 'in...l lry' tI ..· l...Jf·li(.- "f II..• dn,~ 110.. r..I.·.lirnili"lit \h1' ""..... If tI..• 1.., >atM;·
"t..·
....tn.d ,,'n r..ti" cor tl..· .1"'1: i. hl~' . tI..-n "'.", ,i II..· ,....... i. (~",...rt ...1to n...... I..J,It> durin" lhr Mil.. orpti.." .i ,Im,,- ..",I tI,,· ,it..-li,,,· p6. ...,.·..n "'I>ll;l.\ic-. In thi• •iuml.diorll'. lim" ;t1111 n al,,>Iil.· h.o... I,alr-I".... " f :l..'!i..,,,I 1.1lIT. n"'p"'ti\'..1~..,
~
~
~
, -,.,
0
u 10 .~
:8 'i!
I
I I I I
" , ~
E
~
.', '
. , -,
'. ' '; ... ".
:.
r
...
o
6
' "
i!. 12
18
24
metabolin-s. fon m-d on till' first I"l-\~ through rlu- liv('f , C..-rtaiuly, Ollt' idt'lltifit't:l llwta bol.ite . 4.hytlm:l.) p Rlpr.1Il0Iol, is ll-\ acti ve as propranolol . In Chap. 9 (T ablt· 9-2), ('umplt'S of dru gs stan-d to 1M;'IMrtiltlly Ilwtaholi1.1,'1.1 within the ~'l-\tmill!("slillal tract are ~\'('ll . For SOliI(', t...-ideuce- fa\'() ri ll~ thi s sill' of metabolism is the failun- 10 dt'!t'(.i a lIwt aholih' when dm~ is wwn parenterally. )'t·t siPlifil'ant co ncentrations o f thls Illt'talxllill' are meas ured afle r oral d m~ administrat ion. \\'e n ' metabolism to occur primarily wtthtn tilt' Ii VN, 111t'1l tilt' fmd:ioll of tl l(· dOM· 1,( >!lV.. -rtcd leItilt' JIlI'IaIM.!iI..• should 1M;" Iudcp-ndeut of tht' mule of dmg admlnt stmnon . 11I11S, ~w n that in~('Sh'tl dm~ ennrely I mw~'s lilt' ~a.st mi ll h'sl i llal wall and that hepatic rm-tabohsm Is tilt' onl)' route of e ltminatlou. dm~, wln-tln-r W V('1l ol"'dlly or pan·"ft·mlly, is t'f!lIally and fully availa bl..- tc tilt' liwr for metalohsm. 111t' oral bin'l\ mlahility I)f th.." d rug lIlay be low if its hepatic extract ion runo is hi!!:ll, hilt till' fml1ieJll of dose l'tlll\'('rtt, 1 In a uu-tabohte mu sl he mdepcudent of tilt' rout e of dmg administl"'dtitm. 111l' da ta ill Fig. 21- i support th is I'LSt point, ~I OIvh ill e is "i ~hly ami alll1U~1 ..·"d llsin-ly clean...1hy 11ll' livr-r. Usiug .\ t'C as a 1Il("a.s un· of th e amount of lllalt'ri all'nh' rin~ till" IXM!)' , tilt' o ral hioa" ;tilahi lily o f morphine is 1,1'\\' (2 1%). bllt the amount of tilt' act ive lIwtal Mllile , morplJ ilJ(· -6-~IIII'ln>Tlitl .., [orrm...1is lilt' same , when coml"lring n -sults afh' r oral and i.v. dm ~ aduunistrutiou. Ukt.....-ise, till" t'fillali!}' of areas of lIapht!loxyl,u.iil- ,u.'i
CONSTANT·RATI DRUG INFUSION In C hap . fi , llw kim 'til'S of it con stant-rate i.v. infusion was examine... 1. Heca ll thai Infusion mhoand d t'a mlln ,' rh-n-mnne Iht' p lateau e unvnt ration and that half-lif(· alone determna-s tln- tinu- to approach plateau . 111t'S(' ohSt·r\.'atio lis {".I II be- t'xtt'nt!t"ll 10 metabolite. The ('SSt'nti:11 Ii-at u n -s ('lUI 1M;' und t'~hMX I by ('flll si d('ri n~ llll' {'unstant· ralt· infllsion of dm~, Ihe "l:lwllll' n il p. ,'l6S for lJU'talxJlite formation and t"liminatioll. and th t' (...·t·llt5 d"pitirt1 in Fil!:. 2 1-.').
C HAPlf ~
21
1000
1
A
. ' Jt. II- 7. S..hjr"l·h l't"(...... ~noor . phl, ,u.Ifal" ......11)·(11.7 m~~~oIow.I b ) and In t............wy (.5 m~ bIri h ) on .".r>&I" '1IlTL\I"M. f't...\ ma
t.
('(Jfl(..-nlrat!'IR' pf dot( IIral; • . h .l (AI and .....-th~ "",-tal.>I,t... mlJrphi....·6- ltlun ln>ni.1.- (.0.. oral; O. I....) lS) "' ,........nod \,~ .Lola in 10 hfro<11 T1; ~~"' . CT'ntratl<wlI .. f .1nI,t (A l .-od ... bl.. (Sl ..... n",nnaw..d to a ID-n"lt J,.... murphl Iulfalo:- T1wo .Wa 101luwil"lt lmnu.tr-.ot:i1.
100
"",,l .o\i a
-r......... •1 rd......,...
'nt-pa twp.1K- mrtahul:llm . t .... oral \&il.l>tht~ of "''''rphi i.
J...". «F •
1
.unounI
o
3
6 Hours
9
12
of
O~ \.
E,", .... It... ........
n>rt~ ....lr
rntrn I
ctr·
&Io "~ I~ I.... '"J'~· .I A l ·e l ' .M -iaI.... with t.... ........... 00 10:- f..U lIllln.,. I\Ou 1'Ol~ of mor·
('(,t..n.
phtl'" almlnHtndOUll ( I ~!L pht.... w1f.ot:o:- . 3 ..5 1ol \ 1•. UUlarn.... ()d.-uno:- ft. ..-I. s . T"""". D I
100
S.... ;n. M., M phi.... and nM"Lol• .Ltr hrh." iur ..fir, . !lffr ornl n>.. I~ of ""'.-phi .... .tm... j~rah" IN . of"" of Ilwo Itnp<-.t al l .. m ;oh.oIllr " . " -6-(1 ' 0 ... nilI.-. Chn f'twn ~>1 n 4;":12-
11.1. 1""11'.1
10
1
o
3
6 Hours
9
12
The Plateau At any l imt' d ll rin~ t1 m ~ infmiull . Role of change of
melabo lite in body
k,. A
~ml ·
Rote of
Role
metabolite
meta bolite
fonnot;~
elimination
ur, l " pn"!\ \i n~ till' l"fI\l;lfiulI in tenns of plas ma ('OJKT n t rlltinm
AIm!
of
8
METABOlITE KINETICS
378
CHAPTER 2 1
Rete of change of metabolite in body = CLf ' C - CLlm) . C(m)
9
\ \ 11en steady state is reached for both drug and metabolite. the rates of infusion and dru g elimination are equal and so are the rates of metabolite formation and elimination. Equations 8 and 9 then simplify to Amount o f metabolite in
body a t steady stale
=
k ~ • Au
Conc entra tion of metabolite in plasma 01 steady state =
C~%)
10
.
CD
11
As fm is the fraction of an i.v. dose of a dru g converted to metabo lite. the term fm . l\. must be equal to the rate of metabolite formatton at the plateau. namely kf · A.. or e Lf' C... So
Amount of metabolite o t steady stote =
im . R k(;l
12
and
CaseA
3
Case B
3
k < kIm)
k > kIm)
Metabolite ~ ~
2
2
0
"'
.a E
~
0
E
-c
Drug
Drug
Metabolite
o~ o
4
8
Half-lives of Drug
12
o
4
8
12
Half-lives of Drug
F ig. 2 1-8. Two ~itllalion~ rolloo.\in g constant-rate dru g infusion are dt.-pic.ied. In caw A. the more IlslIal situa tion ,
tlk" m.-taholit l'" half·l ifl'" is sboner than tha t of tilt' drug. ThrouglKMlt nKKl of drug accllmu lation, mclabolitl'" I'" liminahon is fonnation nlte-limited; therefore. the approach to the nK"l:abolile plateau is dcte rmtned b)' the half-
life orthe drug. In lhe less co mmon situatio n, case B. the half-life of d nlg is less than thaI or metabolite. Drug is al Sll'"oo, ' statf." w....l1 he fOT{' mctaholite. Approach of the metabohte 10 plateau is 1lO\." df"tMlninl"d by its ha lf-life.
379
Con cen tra tion o f metaboli te 0 1 stea dy store ..
1m · R
~
CLlmJ
13
Suppov -, fo r (·"-lI lI pl.' , thai a d rill! is infll , t'il OIl ,"i lIllV1 IT. f m is 0..'> , kllli l is 0. 1 I. T- I, alill Cl.I m ) is 1.0 l vhr. Then.
0.5 x .5 mg/hr A mo unt of metabol ite 01 pla teau .. 0.1 hr - I Plasma co ncentra tio n
of metabolite at pla teau =
0 .5 x .5 mg/hr 1.0 tlhf
25 rng
2 ,5 mg/t
TIme to Plateau Huh" 1' 111" 11I(Il'.illll , TIl<' li l li" n-quin-d li lTa IJlc·I ••l oltu- to reach " Jak au d" IM·IIl I.. 011 wlwt lwT OT not a holus of tim!! i-, l!i\l '1l at tilt' ..tart of till' ('Oll, tan! -Ta'" IIn l!! iu fu\ioll. If a ho lm is c:in'u aml tlu- illfllSio ll mailllaiu\ thut ,11 11011111 of d m l! iuI ]u- hod~ ' . t llt'lIl ll1'a ppro;lci. of till' Illd aho lih ' towa rd " Jail-au 11\ 'IM·nds flll l ~ ' fill its ha U'.lif.,. T h is poill! 1 1< ,( ~ JIl I \ ' \ apl Mwn l WIWll lll '" n 'a li/ l's that al (,(J1ls1alll d n ll! ("Ill't'u l ra!in ll, IIw tahn lill' i~ li m rle·d at a ('Ill..tau t m lt- ,JIII' /In' .\ s th is i ~ a na logo us to ~i\; nl-: a ('(J1I, la lll · ra l(' illfllsinu " I' lIll'laIH,lill-, il td lnw, arum Chap, fi} th ai tln- a pp road ' ln p lat"il ll is ~o\'l ' n ll'd,·"f, ·fy by till' 1l1l'lalHllih ' 's half· liti ·, T Im., . ."')4 )'1 und !,1W',f Ill' tlu- p latt ';1ll a re rt-al'l wtl ill 1 a nd :1..1 md al Hllitt , half.lin's, rnp''( '' li\l,ly . I k-n o -. rt ll' laIHll i lt ,~ w il l. sho rt h alf·li\l ·s rt' ad l plalt';1ll quic kly , I n fu ..Inn A I" II(' , I I' lin I H .l ll ~ i, gi n' fl, tln- situutiou h men- (' " llp lkah -d. T Ilt' tum- fo r ;1 lIw la IH.lil. , In TO-ad I plal "au cuu IH' ~.. ,,'rll.-d prilllarily by ,'i llll'r IIII' d n l ~' s or lIll' laI H.l ik \ Ilal r· lift' , u·hirl"'fU is IIII' fOllerl', T o app n '('iah' thi s poin t, nl n..idl' r h \O , il ua tiolls . !loth , 11' 1\\11 ill F i!-:. 2 1 -~. 11 111 11- IIIOf(' p n-vuh-nt , it llal il'll, <:;L\l':\ . 1111' tl n ll.!; l ias tlu ,I'>lI...:, -r Ilalf· lili '...h " \ lll'd,',I, 1111 ' ,UlItllIlI1o f dru g ill IIII' h' Hly rmd ll'.s p latl 'all in 'lp p ro \ illlah' ly':3,:3 e1 rug Ilal r· li\ . -, . T Ill' al lln' llIl ,If m l'l al Hllih ' allll lll' II('I' 1111 ' r ate- clr IlIc·tal H,Iih ' 1,lirllillal lllll ..1,,1, 110\\1'\ 'l' r, IlI'(·ar.....' c·lilll illa tiun of lIlt' IIId aho litt , i' a 1I111eh [avte-r prfJ(, ,'S thuu Ihal ,,1'1111' !l nl g . l ile' rutc- of IIlI'la lH ,lill ' c·lim illaliolL \lH'1L 111 '('1 111 11'\ Hml,, '(1 by a nd a ppro\illla h· ly l'I\lla l In ii' rat .. o f Ii ,n ll;lli oll . \1 l'l a llillih' is thr-n a l \"irt lMI ' It-ally slall' w it h n" llt'd 10 . and canuut ri ..t · a ny fa.shor thuu. d rill!.. T h i' 1i,l1ows. , inn ' 1I1111(-r th i.. ('lr n lil io H (E'I ' :\ )
ri,.·".
. Amoun' 0 1 me'oboille -
(kfm) k) , drAmounl of ug
i..... tIll' ;(1111111111 o f Illl'\ a lltlillc' Prol lt lrt iollall~' fI ,Ut 'l '" III(' ;I1ll11IHlI o f IIm g , Tln-n-ton-, IIII' nu-t.. lltllil.· n 'i1dlf's pbte-'Ill wi tluu ap pro\i mak ly " d m ~ half· Ii' I''' , III Ca'" B, lilt' d rill!; j, I'!im illalt'd I;\,,,"r than IIId ahlllill' , :\OW d nl g read ws ' l(';u h ,I"tl ' 11I'1I ,r(' IIII' 1.., .. 1 o f tIll' ll\.'la IH ,litc· I.as hMl' ly ri" 'Il . F llIlII 1111'11 'UI, 11U' rail' o f lIwl ;'dHllit< , fo r ma lio n i, I' m, lan L ;11 11 1 ;l' ,, 1""('\ 1'11 pn ,, 'ioll , I., ', ,, 111'11 a ll .tpprupriau- 111.111, o f d n ll.: i, ~i\ c· lI . ;!("t'ulll1lLtlil lll o f md alH,lil . ' 10 p l.lh'all is c urtrolk-d hy its IMlf-lili ,. 1':\ r ll' 111'l tli'II('I-illalt ' II' 1111·lllylp n ·;llli' (lilllll" n "I)('(·l in '!y. .
Postinfusion :\s , lulu!II III'\\' III' al llidpa lt,(I. •OI l shl l' l,illll; a ll in fllSillll . 11 11' (11·d ill(· of Ilu ·I
31. uwthylpndutsolonc's dccltnc would hl' det emuncd by its half-lift· afkr Sl (jppi ll~ an infllsioll o f its Il('lIIisll(:t.1Ilil lt' ester.
MUlTIPlE-DDSE DRUG REGIMEN Tlu- l'OUet 'pts that apply 10 Ilwlll ho!ile roll( l\\i n~ admhnstmttou (If d m~ a... a s i ll ~lt' dlls(' (I f infusiun r un rt·ad ily hi' app ln-dto lIlt' most common situation of a multipledost, oral d mg rt·~TIIt'Jl . As " 1111 Infusion o f drug. accumulation of IIwl aI MI!i!(' til p la l('1111
;1 consta nt -rate
t1t'pt'mLs us Illll ch Oil its half-lift • ;LS Oil tha i of tilt' p;m' ll l dOlI?;. For exatu ph- ( Fi ~. 2 1-9), al'(1111l1 11aliu!I o r :"o; -<1t'salkylhala7,{·p;ulI . a llll'laho litt>o f 11](' 1ll.·Ili'Hd ian ·pim·. halaa-p.uu. la~5 IM,hind pa n -nl compound du ring d m ~ administrati on and falls mort' slowly afh"r ad ministrutiou is stop pe d. Both Oh M'l'\'lltiolls occu r b(·(."llll ~· th is Illl.'tllhol Hl· hll~ II IUIl ~l'r half-life than that of tho dm~. In addit ion. tilt, plan-au concent ration of :"'-d('S1llkylllaJ.w.'ll1ll11 is
than that of balazcp.un. si~ll i f)i ll~ tha t tln- lIJ('ta),ol ih ' h;L~ tilt' 10wN dt·ar.Ull'l'. Fluct uat kurs ill rlu- pJ'L~llIa (·OIl{'t·lI tratio ll.~ o f both dmg allll llwfa!tolitt· an- tlu- u nly I\I ~ til-t'able difTt' n'JJ('t's (·xpt'(i:t'l.l ht,tWt'!'1lall infusion an d a llltl it iplt' -( Iu~' f('¢II1I'U. The dl.'~n't· o f lIm:tllalioll depe-nds 011 tilt' dosi ll ~ ff('l. llIt'l\(" am i half.lin's of d m g absorption . ![]()
lim inal ioll, and lllt't;lholit l' I'lim illatio ll. h i~h ('r
PREDICTION fROM SINGlE-DOSE DATA Tilt' coucent rutjon o f nu-tabolltc- dunug an ()OIl
lll ll lt i plt' -dn~' d m p; f('¢Ult'l\ cau f('adi ly 1)(' c alculat ed fro m the pla.\lIla ml.'ta!tol itt' (1l!1('t'utr.ltioll·t imt' profile ufter a single o ral dost' of tlnlg. Tlu- ap p roach is analogo lls to tha t take ll for drug alom- (C hap. 7, p . !'l7). Ti lt' IIlt'tal)(,lite ('(lTll'\'lItmtiun lit ally tilllt' in to tilt'
~
§. c
.2
0.1
];!
naiazeoam
"tl c 0
'-' ~ E
0.Q1
•
e ~
0.001 0
4
8 Days
12
16
. 1" . 21-lJ. 110.'(..,.".... il hoi-' tI..· i<..,If'.' 1,.,lf·(;f.·. II..· " "1..1".Iil<· S .. I.....JL"\II.... t..,.. l""" (<>. mI.", I" otl, a'''~, '''"I ...I... "..,... ....1t·".i\1' I~: iU,,1 (••11. "",... .It ",·I~- I I...,-, it. 1"'' ''''1,lno,,- Io..t.llc·I"'''' '. '. •turi",: ",,,I;tfiN ,t"'l'i,,~ II..· i"I: ti.." hi~"'r pt."';tUU""'t'T,tr;tlit",. ;t,,,1" ,,,I..ry;to. , II'K1";tlit.., m ltl' ........I .. ilh I...n·,,' .Iml:. 111.,Lw l"'''O: I '''WI. - 2." 1oI \I ; dc""I1,~n,;tI;Vil"'l1l : 1 "'Wi. - 3.7 101 \1 ). Ilt,..lr,." .. rn"" ( :1"",11.. \I ., 11 , 1I ,, ·rt .J , ~I .. ( ;" r,.l. R I' ., It ..d ",.,." ,LI. E.. S~" K"""'i<'Z. S.. ",,,I ;-.. "'1"'1:1it....-. ~ . : ~1 "lt i l'l.· ..I."'· 1,;tLv,1""" lit"""", <:li" , 11,;t" "''' 'I1. TI,,·r.. ,J.P c1-......... z. IWW _H., ,",,h,,nl " ith p,·n",..it", of c.v. \1 ,...1,:\ .)
.,-lj
')[IA80 UT[
' I NfTlC ~
381
lIlt'laholih ' I'JIlI"lllralillll' "\1)( "('\1,1 fro m ,'adlllf tlu- pn'\iou, tlo'>! " : tlu-n - i, IllI lIt,,1 til 1m,",· allY pl,armal"I.Jlldil' parall1l'h'r of ..itlwr t1nl~ ur lIll't aIMllit." For I'\111 .·\ l'C n 'll\i,I, 'rali'lll' . TIlt' an',l umh-r IIIl' lul'lal" ,lih ' ""'('('"lralillll·tillll · I'UI'\I' aliN a "ing t" .In,, ' o f .Inlg, ,\ l 'O /II J......".., i" 1.,';\1 '11 hy
AUClml
''''9100
=
Fro ' Dose CLlml
I.
whe-n- F... i" II.., fradioll Ilf II" , ad rnilli'!t'r'''I1 d"",·
'I"
qml".a>"
f ro ' Dose =
t ·
CL(ml
15
16
rill' ,',ampll', if IIII' .'\f r/lll ).,..~.,.. i" l ~II IIlg.I,r/l. ati"r a WII'lIlg d""" of dn, g:. 11... 11 IIu1·'I)l"l·lc..1plalt'all lIu 'talM,lih ' reuro -nt rati, '11 i, 11) 1I1WI. whe-n thi s cll'''' i, Wn'l' t - ,' ry I ~ hr. Ohviou,ly. if IIII' 1l!l""l"\t,t1 an 'rag.. plalt'au 1Il1'tal M,lilt' (' )I\n'llt rat illu dil Tc'1'\ [n un Il.,lt ..,. IM 'I1I'd . Ih" 1L dtlw r 1-'"" t'1,',ualln' IIf IIll'lalo"lih', o r 1",111. ha ' I' 1" " '11 alt l'n.. l dll rill~ d troll il' llnll.( al lll,il,i,l n llillll .
VARIABILITY :h will i 1l<,n'III dm l.(, II", pl,armal"killl't k , o f" md"I",lih' \ ari,·, witl"l~ ill t ilt' IMli"lIt IM 'pllbtioll , " 'itIt add ili onal \; lIia h i l il~ in d l'a ralll'l' of ltl1'till",lilt, rim tMlioll . t loi, O t'l I '1I lIt1'i1tl' tllal i"h-rpal i"tll \ ariah ilily ill ltu 'tal" Jtih- " 'Il(l' ul rali llll 1·,1It I" , ,'\I 'll I.(w"h-r thun IIMI \1"1'11 \\i l l, parl'lll tlmg. SOlin" , of \ a n a bility ill 1lll'laI K.lilt ' k i ll l,ti,~ arc' lIlt' " m il' a' lit.. "" ,tIT. '1"1 i It I.( Il,lWlII t1ml.( alld ittdll' I., 1.(' -m-tu-s. agl', eli\l 'a"" , "lid ililt 'rat1illl.( t1ml.(' . l Ji ffl' n'IIl'1'~ l"i,t ,lIll0 lLg: l"'Iil' llh ill IK III. d .. aruno - ami \'Illmlll' of c1i\lri llll tillll " f wd ,tIKll ilt· ;1I 1l 1a.' with ;1 d nl g:il,,·If. pn 'f,'rahly '111 1lIII"\'n! . Thi" 1>('-''' ,"" !)"u1kllb rl., ill lMli" lL t, \\i ll, n 'lIal ill 'Il ITi l'i"I 'I~ . 1101 '1>111\1' llIall~ ' mdal ",lih-' a n ' n 'tati\(·I~ l)lliar and an' p rilllari l~ ' '\IT,,tt, 1 lll,d ,allgl'd . FI.r ,',alllpl, ', t l... " Iiu ,ina lilll' Ill' 1IlI,rpllilll'.li -l.(llll'llrOlIlI!l,. ;11 1 ;lI·thl' IIll'tal " ,lill ' Ill' 'lIlllVhilll' i" n ..IIlt,..1 ill IMli" llh \, il l, n 'llill d y, fm' di llll. J' n ..I,dioll .. f 11ll' tot al adhily .. f dnl l:: a mi dma~1' "dj ll, l lltl'lIl 111""11,..1 in 1",l i"lt h wil li n 'll,11 i ll' 1l 11it1I' lll~ ' is Illt'n,li,n' mor.' 1~ ' lII p l,'\ tl, ,11l " 'Ha l. 1' 11" 11 ' ,In' way' lOr tn-;lli ul.( '"l·h "il ua lio m . TIlt' Illml 1I\1 ,l'nl i, loy IIIl' ' '' ';llly." I'lh ' a p p ru;'I"h. Tn illll"l r:!'" IIII' II'" of tl, i, a p prco,tI"ll, "'ll,iel, 'r II... ",·1"' 11I,' ill F ig. 2 1- 1lI. "I, il-It , how" lIlt' illl'"1 a llli tfl'IMl'itioli o r iI
CHAPTH 21
3 12
00'"
. '1" . 21- 10. \ 1,..1.·1 fur .d"" ''llti..n ... lll ,Ii' p." 'li un "f .. 1 1 ~·pc >t l"'l k .., ,Iml: ;1",,1,li' p..' iliClIl lOr ih ;o<1 i\ ... Tllt"ta h"lit ... Th..ll l'llt numbe r In 1""'''''''th... iJ n-f..rs to the frat,ho n of d roit "r mt'1 aholit.. l hoot I. nonnally ..limi",,1t'J by l IMo pathway . h"wn "'1th loi n a(JOW, The second number refers 10 11>00 l a m" f';K"h o n
wh..n
~
""",,,bOO
•
OntO in
(0.3.0.61
Body
Ih....... II n o
Act. .
Metabolite • Body
(0.5. 0,Oj
rena] (unci;o"
''''''''
Metlbohles
(0.15. 1.0)
(O.2. 0 .4)
iO.t15, O.O)
~ ~
dmJ.: and Its adj\'(· nu-tabohn-. T ubh - 2 1-3 lisls ;\ \'(' r .l V;c' vulues for several pha nuat'fJkindi{-' IMra n lt'h ' n; o f this d m ~ and its ' l(:t in " mt't;tho litt· in til(" I~vi ('al pat tent ....-ith lInim pa irt"(! n'II"] Iuncuou. III thi s (·xalllplt· both d rug am i active metabolite art ' (>t:luipolt'n l and cquitu\k ill t(' n lls o f plilSlllUcone...-ut rauou (wit h £'ileh ill1hit~· a
Cla......
_ 0 .8 x l OOmgfhr _ 27 IL 30 Vhr ' mg
T Ill' mit ' of fo n llalio ll of tilt' at1iW IlIt'l aho litt' is 0.3 tnm-s ti ll' mh ' o f input of the dmg:
then-fon-. l OO mg/hr _ 2 4 I l q mJ....o.. ., 0 .3 x 0 .810 xVhr . mg . III all auuri c p atient . tot al dt' amnl ,(' is estran-nal d l'anUlI,(' , Fur thts d rug. cxtrun-nal d";lnl.ll{,(· i\ 15 l AIr: for IIll'la holih ', it is 1.5 LAir. Therefore. Ihl' p n 't litit't l ste..
qdl
...,.....
• 0.8
100 mg/ h, • 5.3 I L 15 V hr mg
X
R''l';l\ISt, O.fi o f lilt' total ,'!illlillatioll, ICI4/ (Cl . - e LI! ) or 9 l A lr/(30-- 15 ) lAir ) gOt'S to 11Il' ali i\'{, Illl'taho lill' in lilt' unuric pa lit-nt . thl' slt'ady-statt' concent rut ion IIf Illl'tabo litt', G( iliA '''.
M...ltellte Toto! ciecrorc e Reool cleoeooce FrQdl(ltl e. oeted UIlCho~
0 01 BoOO\IOilob,l,Jy "Ct*"""«l1obo,"9 o d o - _ ~ .....,.,.,... "1<0<_
~ <:hg ~ "' ......... '""*>t:oI
30 Lltw 15 L1tw 0 .5
08
10 V "'"
8S Llhf 0 85" 0,31>
CHAPTER21
M.. "lAl\Ol.rTE KINETICS
qm dl •
P ,,,,"
313
_ 0 .6 x 0 .8 x 100 mg/hr ~ 32 / l 1,5 V hr mg
:-';nl l' that till ' lI\1.'m.L':l' dnl.L': l'Olln 'utmtio li is twice :t~ .L': n 'at ill Ihe anuric patient. wh ilt, th e itl1in" lI11'tliho lill' l unn 'nl mli oll is inl'n'iL\t"t! 13 ttnu-s. \\'ilh d rug and al'th 't' meta bohn ("tluipu!t'llt and adtliti\'t, ill t lw ir activi ties , tb l' r ate (If ad mhustratton in the an uric pa lit'lIl should be (2,7 + 2.4)/(5 .3 + 32) o r (1.14 Ihill of normal. Thus, the anuric p atient wo uld n -quire o nly 14 mWhr.11lis e cunpk- Illustrates d t'ar ly thai although a uwtalMllitl' lIl il~'III <1k, ' " minor l'tlllirilm lio l\ to tilt" tot al acnvrty in pa !it'nls wit h normal n-nul fu nl't ioll, in all unuric pat ient . it Illay he pri marily rcs pousibh- for al'thity.
ADDITIDNAl CONSIDERATIONS Four o the r a.~flt-'(.is of u\('taholilc kinenes wa rran t 1't)IJsi
Response \ \ 1I('u " II illii\;ly o r to)(id ly n -skles wit h a part icular IIIt'1aholih', rd atill~ res pt lllS(' In II\('tabolite coucentrution is 1l.·la liw ly ~ I mi~h t fmwan l. 11 11' problem is more d il1k-lilt wln-n IMlih t1 01 ~ and lIit't aIMllih ' contribute- to m.ihi l>· o r loxid l)', Occa..ionally. il m ay hi" possih lt' 10 n-lan- tilt' n 'spt)IJS(' 10 a lun-ar o uul unanon u f IIII' pl.tsnm conceutratlons uf d nl~ and rm-tabolin- ll-" "11.~ dom' ill ti lt' h..l sec tion. ~ I on' often, ho w ev er, the relationship Il(·t\n 't.'n n'~lxlIls.t" and eonceutrutjou is mo n - complicated. am i uo simp!I' n-lariou slup exists . Fo r example, if till' n.·sIMIl\s.t' produced hy ti ll' dm.L': ,,1011(' approaches tilt' maximum, E"",. , ti ll' ft'SIXlIlM" d l a ll~('S hu lt· \\ilh i1K'n ''''' t'!; in tilt' ("I l11l"1'n lntlion of II Illl'taholil(' lhal ad s ;l-.. a I'lJlIlllt' til in ' a~on ist , Ah l l ou ~1i there an " lIlallwmal it',,1 ap pmad lt' S to this probl em. 1);1<;1;'11 for example 011 modiflcanou o f Eq. I ill C ha p . 2U ( I'han nal"lliogi l' Rt'sptlll st» t1lt'y all.' unlikely to 1M' 11<;1;'11 d in ic-.ilI)·, :'\Ulll'tllt'lt·ss, measu n-nu-ut of an act fve Int·taIMllilt· l"IlIlI't'IItra nou can help I" explaiu an oh~ 'n11I i' J11 an d account for \'a riah ilit)-' in d ru g n 'slx lII\t ', :\1"l"l lnlin ~ly, slldl II1I'a.s un-meu ts ca n wrvt- ,l-'> useful sl'm i1lu,U1 titillin" ~llidl'S to Ihl' r.lpy .
Interconnnion AlIIlJll.L': the hst of t111'nI(lt' lIlkall y uupo rtaut 1IIl't"IMllih 's iu Table 21- 1 aft' souu- tll ,ll all.' bacl.. to III(' ad m iuistt-n.'11 d m~ su!JstmK"I-'; they iuclude Iln'll ni<,(.. lone, 1(.1' lIll't al Mllih ' "f p n-dnbom-. ;lIld slIlim l!e s ulfidt" till' IIll't alMllih" o f sul iudac. Bo ll. t1 n l ~ aft' prescri lxxl a... anti-inflammatory
Metabolite
1
..
,
WTA.80 UTt KINET ICS
CHAJ'Tt11 '1 1
,.ltl. 21-4. . . .. ,.....tott•• Drv•• That UIHh.... M...ltellc 1nten:.......I••
(','-r. ""',
.' b<
oc
(,'
,>
Dcps
H(] :P,H'~
'" "'.:'
.
',' rh,1:"l.'d' sc f' ..+
r-e
,'.',,- ,<:--
,,,
.,J' SC
?'C'
'1~"
......."' _
~
Q:J.I:,. <
~_~"""
0<"..
~
0
d~l<>'e
~0Id>,<J>'" ,_ _ ~ _ Iotu. .. I.,do~.-j., """ ."'Q'OPO"'Od ox.d
~ d.i_ a> "d
~,"""P'o
.....< 1-" ~ I..,rl."",,,,,,,
"-' '''9 ~
awl """"" J.>o
.. ill:. 2 1_11. ( hK" "I'"lil,""", j . ....' .lloh,I....1. II..· u ..... ·lI'r-~I ...... .d.. an' 1;oi' I..h.·r ~ . ill":" · nr-..J ,It....• nf .'!Ill "'I: pn.I";" ,,,,· (""I, I "'KI "" h - .10....· " f 1'".lni."I.....· (1; ..-1... ). ..., 1>n. I"i"oI." ..• ,u...iu.,h · l ·j.U n,,~) . I" M•.,IJjo't1 n" " ·I"'r..... "n~ ..i<".. _ 1" . Ir" " ,,"....· .".:,:;,,,,10', 'KlI: , I......" . j, 1,~t1 n>ly'u l w~ r"l.itl~· I II I'n~I",,..oIt,, ..· (l "'l{i l. l,"~I"i"'''..· - 2.'~ ,, \ 11. d t" ["",,. 1"" 11I' II.....-. J V.. ~' '' n ~ ~,l . , \ \ 1.. J". lm. \\ J . "". 1 1~,", ·1I . 1>.; HiI "" 'w la"ihl~' ..Hoi oI"[...'lit,,, ..r I'n~l"i ..... ",,·
1.0
,.I,.
,..hl.·1< 11" '1" ''' 0 11 D o ,1o: D" I' " 1 :z.l7-2~' , llf'll Ilt-l' ri "I. ~1 I~ I,, ·oni~.it .., "f J
0.1
0.01
0.001
o
B
4 Hours
12
ME1ABOtrH ( INEllC5
CHAPlH11
3IS
Eadl pat l l \\ ,l~' is d larad t'ri zl'tl hy all iL\sod a!t't1 cleurane-, am i t'iK·h spt'd t>:; Illay (lilTt'r ill Its \ -II I U lIlt' of distrilllli ion . 1111' lenllina l l.alf-Iife of tht' tuterconvertcd pair is it !l~1 )rid of all tlwse llilr.llllt'h-N. T his S,",WllIt· n-sem hles the 1"\\"fH ,,{lInpart lllt'll t dhtrihlltin ll Illtllll'l diwusw-d ill C hap. IH ( Fi!!. 1 ~1 ) . t':\('(' pt tilt' hm (,,{)lllpartlllt'llts no w represe-nt ( I m~ and lIld aholih-. 1111' dilTt'n 'lIn ' 1)('h \l"{'11 tilt' 1"\\1) lllodds is tha t \\i th Iutercouvi- rsion lo s s t-au al<;() occur from till' "pe-nplu-ral" (nu-tabolitc] {,OIlIpart lllt'lIt. ludced , if no Sill'll loss occurs then. \i t...\,,,1 From d m~ in p liLsma. thl' nll'tahnlitt' is t·lTt't.iiwly a component of d m~ di stnbution viut't -. under tlu-se- circumstances, 110 t1 m~ is irn,\"{orsihly lost via this pilt h\\~IY. 111t' tlw mpt·llt it· impo rtallt"(' o f Interconwrskm varies wi th the d rug ant! Ihl' circumstam"l·. For t·\i llnplt '. illlt 'n "f)lJ\'{ 'rstoll I)('h \l"{'u sulnulac illltl Its sulfidt' ln-lps to mot!t·m !t· ami sllstain tlu- t"llllt"l' ntm tioll of adi\"{' sulfide. In contrast. mterconverslou 1)('I"\\l"{'1I th e aut ih-protu- t1 m~ t!apstlllt· and its It·ss iI{i iVt' IIw lalll)lih ' lIlolltlilt:t"tyltiap st)IJt· has 110 tlu-raI)('ut it' n ,lt'\'allW ; till' equilibrium is ulwavs stm ll~ly towa rd dapso lle. wh kll is pri mari ly I'Hlllinilft'tl via pall l\\'I~'S ot lu-r titan X ·:tt't'lyla tioli. Xonnally. lnterconwrslou ht'l \\l 't'n d ufihri l' add (dt·ri\,.'tl Imru till' rapidl l~drtJl~'S is of tln- admillisl('ft"{l t·thyl es tr-r, dofih ratd am i its ill
o
300
"·if!;. IH-U.. r lll . ,,,,...1d ..·""",,,,~· ill p"liI'llt , " i th uIlimpoU" 1(0) .." ., t~ ""lm Klli .. ~ 1 . ) n·'....J fur..... li.." i. ,I ~,_ h l. K'~' lilllt· d" fihric .-;...1 i' .."1 • ..-n-l,... IUIK-J,anlo:, 1 if~ l l - IHlfi In 0 ,I ) " I. " " ·nil f",...1i,," i. """'....J. III.· ,1U1•• 11...1d.·ara' · " f r~,.. fill rit·
o o o o o
...·n"" (·"·ah"i'N· , i " ..•
• "N'''''''" ''''/"
"."..! f,u "
lilK', Tle- appan'''1 '''1'''r''''''IJ<~' of t-loJi hril: .....1.· .h' l"...ilit,,, ill .. .,....J f;lil,,"·
","I Ill"" I'· ","Id'""'irI..,·r tl,,,·....·. E"" ,, J, e li", l'h,m nam l.. IS:.l4 I_147. 1\l79 1
o
o
5
10
Serum Creatinine (mo/dL)
15
( H....PTH 2 1
316
Estimation of Metabo&te Formation From P la."m a ~ letaJM)l il t" ('..on{'t"n (ralio n. 111t' amount o f adrninis!Nt'() d ust>of d m~ convr-rted to svs n-mlcallv acatlabh- IIwl ahol itt' ran hI' cak-nlan-d if IIldabo!ile ch-arance, Cl.( m ) is 1(IJ(~\ll. Silll~' this amount ('(Illals tl.t' amount of TlIetaho lite elunlnated. CI .(111 ) · A UC (m ). To g:ilill all estnnnte o f CUm ). till" IIlt'lahn litl' urcds to he ~H' 1l intravr-nou-dy. I n till' ~(, l ll' ral l~d.<;I· . lilt, rati., C I .(m ) • A UC (m )/ l)o"p ~ n's tilt, fr:ldi llll o f ,u lm in _ tstered dm~ available systc mlim lly us mdahnlitt' , This rah n 1ll1l)' I ~· Inw, ('.J.::., if a (' tllt'Y llil\"(' a 11l11l'h hi.l1:l.l'r ch-arann' , smalle r \'olllmc' of distribution. ( I f both. t·olllll;.m ....1....ith pan'll l dm~. Bt-c-all. when for malion is mlt'·lillliti ll~, llS a reasonable apprll'l.imatinn dllrill ~ tilt' n-mnnal ph:l-"C', 17
Rote 01 metabol ite excretion - Cl f ' C ROIo of metabol ite formotion
l1U1s, hy mt'il-Sllrill ~ tilt' rates of oxen-non of IIlC'lahulilc' am i tilt, l'C l m'Sllt md i ll~ plasmn « mcentrauon. dt'a r.ml'C' associated " i t II fonnation of 1Ilt'lalxllih ' may Jlt' es timated. :\"ol l' tha i ,,11l'lI Eq. I ';' applies. tllC' fall ill l1It'!aho lih ' l'xl'relioll run- is dc'le rm illl'tl hy, am i can I" , USf.·d 10 t'~ti fllalt·, tilt, half-Iifl' of till' d r ug. El luati oll I; is mos t accurate under stc'atly state condutons . dm~
Dtttdion of Chaages I. PhGfrnocoklnetks Comparison of dm~ and nU't alxllilt>areas is helpful in idc'lIlif,inp: lilt' {)~,11 1 u f d n l~ melaholislll (i.l' .. g,l-"twilltc'~li lllll truct . Iivc'r) wlu-u { I m~ ts adrn inislt 'f('t l h~' t1ilTl'fc-nl routes
Ta b la 21 .5. M aa n Phar lltacak lnat lc Data for IloloriJlda .5-Mananltrat. Ahar Intra v anoU l AdMl nlltratian o f 5 1It9 o f b a lorbhla.5.Mo nonltrat. and b Ol o r.. lcI. Dln ltra t. - an Sa parat . Occal lo n l "'IHISQSC::*flCJt
"'lU~
060
0 37
~~Ul!
AUC Img-Il'/ ll
Cl il/lu) Half-life lh.l
~1rom~ .P
D"II !lA1f ~
83
' 2 ~, I L
orodScho M liooo'bodot~"""""""'_orod~~....,...".,_ l,_.Qloo".....,...,.,."orodoool'*-'9 ( "" ~01 It.oo 30" 8~ "91 198<1 -o-""""~, p atdGoiootl> . IL ~
CHAPTfP 2 1
it d mngt· ill tlnplaarlllHeokim't ies of a d nl ~ or mdaholi te , Suppose , for example . thai whell ~\lm o rall)' till' plasma concontrunon o f a d nl~ of low clea nuux- is n-dnced ou O('C:iLsiOll B compared to tlu- ,"ill lit' 0 11 Occa sion :\. Po'> sibll' ('\planati olls an ' : rrdno-d oral bio.l.t\ll.i1l1hilit)', incn-ascd d eari lllt'(', or hoth. E Xillllillil!iOll o f t1m~ data ulcm- llli~ht WH' a d ill ', hut the sitllatioll is Iwlpt 'i.l (,(lllsitll' rahly hy simullum" llls list' of IIlt'taholih' data. ·n ll' roll ll\\in~ r-xamph- is th at or u s i Tl~l e t111Se or dm~, An anal (),,~uu s allalysis can hl' t'\ !t'Ill!t.,1 to sh' ml)'-state o uulinons. Foll(}\\i ll ~ a s i n~!I' dose. til(' are:l ratios for d m~ ,II'P
(p . 3, 6 ). An ';l ;lIIal) ",is ('1111 al'>!) I"" u....'(1 to examine possible rause-s of
\\ 1 11' 11
Occasion A; FA ' Dose - CLA ' AUCA
18
Occa sion B: Fp, , Dose - Cre ' AUCp,
19
Occa sion A: fmA ' FA ' Dose - CLlmlA' AUC(mIA
20
Occasion B: fms ' Fe ' Dose - CL(mls ' Auqm)p,
21
till' sau ll' do ....' is ~\l' lIll11 IMlth l",-'(.'asiolls, 22
AUqm)8 _
23
AUqm)A
ami Sillt'(' fill ' Cl . = Clo"l hl'n
24 AUC1ml ] Ei.L [ AUC 8 - CLlml8
25
t"{lIlsidN tilt' va rious possihilitit·s. I>ossihilit), I . Re d u("(.>(1 b inanlilah ilit)· t hat i.. due 10 Incomple te d issolu ti on of d nl~ ( f l\ < f , ), If thts is .so, a..s dt>armll't' of neither drug nor metabolit e is aln-n-d. it follow s from Ells. 22 ami 2.'3 thu t :'I: ll W
Elpt'C.'llIlilln:
AUC, _ Auqml,
AUCA
AuqmlA
Th at is, til(> rat ios of an-as o f d m~ am! lI1etabolite should be l"llua! and les s thau l. O f ('fIUN', tilt' n';l-'>! lll ('fluid illsll I"" lilll' to tilt' patil'nt's flti! i n~ to talt, tilt' tk)S(, us instruct ed . a {'(llllp!iallt'f.' probk-ru. Po ....ihilit)· 2. Int'rt"a '> l-d clearance or drug (C I. a > Cl~,, ) , If this is th e reason for tl l(' dt 't,rt',l-'>!'(I d nt~ eonce-ntrutjou. then tilt' expt't.1 t't 1 outcome fur til(' Ull't abolite ( 11 ·1'Il.' nd.~ IIll
MflA.8OJTE KINETICS
OtAPlH 21
till' Illt"t:hanisllI n's po nsibl,' for tilt' ill('I1"('il' ill t1 m~ dl"lr..u ll't' Iliinw!y, tlt-'C:rt"\L>;('(! hillliing of d m~, l'U1)1111' iudncnou. o r inl'n 'lN '1! n-ual dt',U. If Ihis O("(1 Irs , CI 1 is ill('n ',(>;('(1hul fm is IIlMItI'n·tI, hl'1',l1l~" dl·'lr..i1l('t' s II)-' all Jl;lfhways o f dm~ (,Iiminalio n art' t't l' lil.lly alTt"l11"t1. As neitln- r hi();t\"ailahi hty nor lIll'taholit(· ch-a r,till"(' is aln-n-d. E \ pt.·c:tal io n :
!
UClmJj > [AUClml [AAUC s AUC " 10. f:n=Ylfll' h lll1ll1ioll. If tllis
O('C1 Irs ,
CI.(, may or lIlay
1101 dlan~(' d( 'p" lIt1 i n~ Oil
whkh IIld aholi<: pall.\\"", · is
indno-d. Hemem wr, tln-n- is ofll'u mon- thau 0111' <'111)111<"
n -spon-dbk- for
drug me-
laholi slll , am i all a rt' no l ("tpmlly slI."(1'plihlt'lo tuduct iou b,y a wn' n ifl(ludll~ a~I'Il I . t, I . Fon lUltiHn of IIu1(//Jo !itl' i,lllmn/. Sinn ' CI is im:rt"L>;('(1. il follows thai 1 Ex pt."c:la t io n '
> [AUClmJ] [ ~] AUC e AUC "
tln- Illt'labol ih ' an-a rari n d l'l1l!-:t'.. tlt'IX'luls (Ill Wlll'tl ll'f or not Il.t' IIwtal x,!ilt' is til(' o n!y pal IIway elf d m ~ clhulnation. If it is, then. since fm I and cannot iU{"fC"\L"C furt he-r, 110 d lal\~1' Iutlu- IIll't alxl!ilt' an-a ra tio is t'\jx't.'!l"tl. Otht'l'\\i w ,
\ \ ' ld lll' T
=
Expec...at iou . AUC(mls > 1 AUC(ml" 112 ...\ " o tl ll' r IIIt't"bo!it' Ilf/llm'''y i lld lll'rt/ . Si1\(1' CL, is nnl d l ,lll ~t"ll hu t fm is d("l'fl"lN "t1 (as
CI. h il1ert 'a"''1Il, il fnllows th at
E xpt.'d a litJU;
AUClml' ] > [AUC(m)"
I
UClm'j _ [AUClmJ) [AAUC 8 AUC " c. I II('n '(", ('(! n',wl rI/,(lmlU~ ' (e LI( i ). Tlu- Ulltt'lIIW ill te rms of till' llll'lahnlih-' is tlu- sa U\l' a.' t hat pn "tlil1t"t1 fur I " "(,
('il-O;('
b2,
:II,
/liTA8OUTE 1<1Nf.T1CS
(HAiTH 21
AUClmlA,l' l < I [AUClm [AUClm'j _[AUClmll AUC 8
AUC
A.
Fmm tilt" ahu\l' anal~~... il is apran'n l that 1ll11ahulih' ILta Illa~· I.d plu Il compbcan- till' in terpre-ration. :'Irr:ulu i lh\ lamlinJ;:: ..uch tl)lIIplic-"diuns , it is often (X......ihl•• to 11m".' n· ......mahlt · (lJII. du..iou.. a... to tiM' likdy can.... o f a dlaJl~t- in .Im~ plaannatlllindio fmm ('llllhillt'li .I nl~ and 1ll(101holih' data.
STUDT PROILIMS (Answers to Study Problems ore in Appendix 11.) I. Elson ('I al. U-:I... m. J., St n Jll ~, J,M., Lee. \\".-1\._ and All..in...m. A.J.: AnliarTh~t1l1llit' (XIII-IK")· of :'Irr: .at.,'~ lpn ){·.Li Tlam i( It· . Clm. phan nal' ll. Ther.. 1;':134- 1-10 . 19,5) (ltil'fmilll'ti tilt" ratiu of plasma (llnt,·nlr.dinm of a.:1i\l' 11It·laholitl·. :'Irr: . al"t. ·t~ lpn ){"li n;l m id, ' Isee- Tabh- 21- 1), alltl proeainumuk- in patient s on Il)n~-h'nll pn){-.ullallJit!l· d'l'r.'r:-'. Fij.,,'1In' 2 1- 13 i, a Ithhlhrr.UTl of tilt' res ufts of 3.1 p;.lli,' ut~ ; 1111"n- is um..itk 'mhll' \' Iria!tnll . G i\'('u . ;t .. is Iikdy, that Ihell(' values an' reasouabh- ."tilllOllt'S nf lilt' mtin ;11 plateau. UIIllIll('111 nil ",hid ) phanTlall ,L.illl'tit· p
~
j 10 '" 15 ~
~ E
~
z
"i~,
5
01
23
456
N-AcetyiprocainamidetProcainam ide Plasma Concentration Ratio
21-1 3.
WT ABOUTE ~ TICS
390
CHAPTH 21
2. \ \11k-II (i f ,IllY) of IIII' ,oxplanaliolls offered h...Juw ;t rt' (is) constsn-nt wtt h all im-n-ase- in tilt" ratiu of ,\ l/ C(III)It\ UG a rk r 11 s i ll~I (· o ral dose. a. Induct ion of the lilt'lahulil," Ionnat iou pathway. b. Heduct ion of th e volume of di stributioll o f t il(' IIwlabolilt', c. 1III'rl',l-<;(' ill doS(' o f dnll-!: ubsorl x-d. d. Hl't lll('fioll in t:lt'a r.Illl1.' o f an altt'malin ' pat hway of !·Jim in at io ll of d nl ~. 3 . Carba llm:t.t· pilll'. W, l l-t·poxide is a n ucrive a mi slIbs la nti\'t' IIlt'ta bolilt· o f IllI' illlfit·pi . leplit' d n , ~ (·arballl'l7.l.·pine. U sh'ti in Table 21--6 an- lilt' II W illI slt 'ady-sta ll' plasrun coueeutra tious o f ('a rhalll;l7A,' pi lw and tilt' ratio o f th e nu-un ste ady-sla h' pLl'illl
cent r ations of car bamazepine- tu.l l-epoxidc
all{ ll~trba lll 'V.l·pi ll l' fol [o\\ill ~ i lle n.·il\ i n ~
dail~'
dust'S of l~arlli,maz'·pilw. Giwni llal l"iIliliUll;U.l.·pillt· is wel l ah~orl lt"(l. and that tluclea runce of tilt' epoxide, to lilt' diol, tlOt·s 110 1 d l a ll ~I' \\i tll tilt" do~' o f carluuuaze-pinc, what pharmaeoktncrk- pa r.llnt't en; o f dmg am i erw)),;ide nwtalwll ift' han ' ehall~t'll tu explain till' tlata ill Tailit' 21-6? T.bl. 21 . .. M_.ItetHIy Ce_••IratI•• D... f.II
Dot,emoreplne cee Imgl
C.
1
_
.1
. .pl_.MI D.lty D._
C
100
200
400
800
1200
26
43
57
73
00
01
0.1 5
0 17
0 20
0 21
Co
CCltlCef'lIfQ"on [mg/ll Rcro01 Co,bomozep;ne . 1O. ll e spoeoe to Cofbomozepine ~_ I 0.. ~
"-..ood ...... aopoodO
8< /
lMltte PI__• pl ...•
8 . Soooo l" ~ GI ~ Gorto.- ~" ~ """"""""" .. ...... 33611-61 .1. 1m o..."'W1~• .l. l J,.M
"d,,"'''' ~ pfto<"""""lI'"
4. Eidll'IIMUllI t·t ill. (Eid wUI
AU( Img--h'/U ClIVh,) HolHile(hll ~"""'SotooN. p
0..
~
0044
0. 22
23 0
I.Q3
182
c.::o.o.u.. i l , ondSdn<>.M ~ ~"""o .... ond~l.....,....,....I.-.dt.~ond~dc-g
The< JO .l.8 j..,( 91 . IQ8..l.
oo.., loan ~, p ~c.::o.o.u.. 111
~ <J,_boocJ,obboI.., l. ,,,,,,,,,~~ ....
0.. Pto-xoI
n.
38 14Q-l .1. 9 19l1~
META80UTE K1Nf OCS
OW'7E R21
391
a. Caklilall' 11u- fract ioll (If isosorbide d inilmle mt'la!J,oli n '(! 10 rln- 2·mOll1Jnilmtt'. h. \\llal assumptions haW' youmade in your c alculation? e. By reh-rem-eto Ill(' {'u ITl'!ipo lid ing: da ta fo r the 5 -llIl)lIollilrall' pnl\idt'(l in this chupIN (I" 3-')fi ), what l'N.'n 1· nt a,ge o f i.\,.-lId minisleJ"t'(! Isoso rlnde dinilmll' is eltrutuated bv dl'-nilration ? , . Dollt·n.' ('I n]. (Dollen.· C.T.. Davies. D.s., and Co IlOU\" M.E.: Diffe rences in the tnetalMllis~n o f d m ,gs dt'I~'lldin~ UpOIl their routes o f ad min istration . Ann , ;\I , Y. Acnd. Sci .. 1, ,9 :In'i--114, 1971 ) exanuned tilt' inHllt'n("(' o f route of admhustra tion on tilt' metabolic p m fil(' Ilf ho p rotN t' lIol_ 111ls IM'!
'~!IJl:Er-o
eon
lSOPllOTHINJI
i_~
0 01 Inhola~on
s.
6 22 63
'0
cC>VO'. 0
""'''''' ISO"lIOTE iENOI
~.
,a s
130
6 2.0 893
""'''''' lSOPllOIEiliNJI E.3
'6
00
4]
a. O n a tlOSt· h;lsis, isoproterenol is much less act ive in hlCT"l;'a.~ing hea rt mil' gin'lI oral ly th an intmn 'nuusly, which i.s dllt, I" a pronounced ural first-pass lIll'taholic Ins~ , prindpa lly by sulfatl' l'lmjug:atioll. Com ment o n III(' Iikd y primal)' stte for con]ugation of isoprote renol admmiste n-d o rally, b . 1)0 tilt' data SUp pli rt .Uly l'\idt' n{'t' fur Ovmcth ylenon occurri ng presystcmically folIl l\\i n ~ nrul ad lnini.slmlio n? c. Gin ' n the rt·lat in ' similarit y of lilt' ex{n·I0I)· profiles (ollO\\i ng lilt' nral and Inhaled r outes . comment Oil tln- likt'l)" fait' o f much of lilt' lnhak-d d rug . U sbortu- e-t al. ((h IMm w. B., JIM']' S., T rew, D .• and Slt...-in , ~f. ; ~ 1 (Jrph i lle ami metalsutil(' ht·ha\;nr afl N tlilTN t'nl routes o f mo rphine administration : Demonstration o f tluimpo rtance o f rln- act ive nu-tabolttc mc rp htne-s-glucororode. C lin. l'harrmnol. Ther. 4.:12- 19, 1!1!1() s!ud it'\ l tilt' I'llarm:ll'llkiudil.-'; of tilt· allal)!;t-sit,: lIItirp hillt· ami Its !"''II ghll'Um nid (' nu-tabolites . rlu- adiH' morphtne-a-glucnronfde. and the inac t ive mo rph ine-3-j!lu(·uRmide . Tablt' 21-9lisls mean ( ± SO ) A UC am i C..... data obtai ned fol. ll)\\i n ~ uchrumstratiou of morphine sulfa te us an l.v. bolus (5 m~ , o rul tahlet ( 11.7 m~. und sllhlingu al lahld ( 11.7 mg ) 10 10 heallhy voluntee rs. ~ 1 ()l a" lar wt'igh t of morphine is 2S5.3 WlIlole; mo rph ine sulfatt'. 669 Wmo1<--. contains 8.S.3% morphi ne Illlst'.
,.ltl. 21 -0. M. ... ( ± 'DI"'U~ ..... C-l' Data- fer M-,.hl • • ne.I•• A...I ..I.trwtI_ ef Merphl_ II' DHter.-t .....
ts Glac._..lcI• •
•• llCllll!>
lv'orph,ne-O
glucuromde tYorph,ne-3-
glucuronide
AUC Inmol-hr/l1 C-. Inmol/ll AUC Inm
229:!: 273 :!: 313:!: 80 :!: 1765 :!: 407:!:
37 65 87 15 300 100
43 :!: 21 % 37 1 :!: 84 :!: 2 180 :!: 440:!:
13 7.7 159 26 808 125
48 :!: 10 19 :!: 4 5 2Q8:!: 159
74:!: 19 166.4 :!: 485 386:!: 8 1
.vtTA8OUlE KlN£ TlCS
CHAPTER2 1
a. ( ;a!ellla!t· tln- hiuiw ails? d . () III' n';L<;(JII for th(' list' lIf sll h l i ll ~ ml ta blets. in V;1·lll'rd l. is til iJlt'n'aw tilt' !i)~!l' lIlk hil);l\";\itlhilily of a d m~ Iha l l',hihits a t.iV;h fi rst-pass In-pane loss. iLS hlood pt'rfusinv; ti lt' hut1:al (';I\i l>' dr.u ns din'(11y tnto II\(' Sllj"N:'rio r \l,'11ii cac u . Do till' clnta ill Tuhle 21 -H sup po rt thi s nltion;(!t' fo r IIIl1rphilll' ? e. CorllllWll1 bm-lly as to wh at 1'\!l'1l1 lilt"('sti nmlion nf oml hit);IHdlilbilil>' of mo rp hint· I ml~' he 1/<;('(1 In ,guidl' ;1II~' di lTt' I'l'nt" in dus;(,g(' rt"t lllirt' lllt'llls u f morphine v;i\ l,'n u r.llly am i illtr.t\l,·nollsly. f. StI~I 'sl why the- C.-t fur lIl11rp hilll'.;}.gluI1Imnidl· is !-tn.,tlN tlum that of mo rphine. afu-r i.v. 1Il11'llhi lll' admiuistration. ,g. Ind t'I"N:·llIIt·lllly. O sholln w l't ul. (O sho unll' . n.. Tlrompsou. .... [oel. S., T rew, D., l'un-l. x ., am i SII"\in , \I. A.: 111l' ;lIlaJ!-tI'sie adhi ty of lIlorphillt'.fi.v;lul·unlllid t' . Hr. J-e liII. I'lurmacol.. 3-1 :130-1 3-'\. H)lJ2 ) studn-d ti l(' pIHtrl llal' lkint'tk s u r mu rphillt'· fi..~!m·l lnlllidt, artt'r its i.v. admiui... tnmon to t~lIIn'r p at k-nts. (; i\1'11 th at t jn- dt'ul'lmn' fou nd, 5 .~ 1./1Ir, ap p lit's to tilt' \ul ullh"t, rs who partidll