Cl i n i c a l Pha r maco k i n e t i cs Con cepts ond Ap pl i c o t i o ns

T h .1..

On _

I""1111111I11111I111 1111111: 111111 11ALOS- 706- NZWP

Cl inical Pharmacak inet ics Concepts and Application sthird edition

MAL COlM R OWlAND, Ph.D.Depomnenr of PhormocyUniversity of Iv\oncne$ler

fvlonchester, England

THOMAS N. TOZER, Ph.D. School of PbcrmocvUniversity of California

San Francisco, Cclnormc

A Leu ..... Febiger Bo v ok

.e1~ LI pPINCOTT WILLIAMS & W ILKINS A Wollen Kluwef Company

Philadelphia Ballimore New Y ork l ondonBuenos Aires Hong Kong . Syd ney Tokyo

f:.w .: uIIH'

f:.I.,,,,, !)""'..l HJt /-:.111"" J(oh." lJ .1I'1tt, (

Copyright C I99S

lWHO ~01

~r, lI ..m. ~ .....

l!< ~'i u.,; ...

Pt"l.Jdrh'" lm yInft .. 1'1101'>-:1021 l ' !>A

All rilt~ re....'rved Thi~ h"

Blood flow, 1) lII ill CIT 1.111 1'. I>i 'lly~.ah How in IltlIIullilIJ~ ...isws n-m . ml Jmill (II' IAlT. Hall ' of filtm ltlI11w 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

of ( Ii~t ri htlhon (al'lp .. n 'nl ) tlm l?; (llIK'l"ntrollitlll ill ptl~III'l. L

\"ululllt' of (listrilK ltMIIl (a pp a n 'n t) b ased on ( l rtl~ (1l1l(1'ntm fio n ill

V/ V.. e

I'

blood . L BlocM volume, L, I" ollllllt' (If d iah'!lall' solutio n (111 It'(1t... duri ng ~ helllo(lialp i.s 1 tre-atme-nt , l ;\"Ullllllt'

\'"

lA,r.Hiltin of conc eutra nou ill blnnd (, '11 10 thdt IIllhutllltl in plasma..\ ("(.'11111111a lio l\ r,olfiu (imlt'd . 110 uui t...

",\ '".\ '( m )

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.

"&I1ft'

Ratio o f u nhuulJ(l c k-aran o- of an

Individual patk'Il1 In that or aKW panem. IlU units . M

~p-

1("

Itt- nat fUl K.1KIII in .III indi\iftual p;. itnl a.~ a fr.K1iun u f n-ual d flllK.1iou in a t~'Pkal l);ditnl. no units. It l le uf l'tlll~tani intr.l\l.'nul!S infll ~ioll , 1IlW'1r.

\"olllnl(' of di strihlliion (ap pan'lI t) o f a Illt1 aholite 00.'\(...1011 ih pb.-una (' "K't' ufrdlkm , r,PIa.~lIla

I 'r\ 're

volume-, I ~

\"OIIlIlW of dial)"Satt'"ithin lilt' pC'rilulJ(ll! cavi ty, L. Ali"ttlIlS " U llllll(' of illll'al,'l1nlar fluids. I ~Pt.)'Sioll~c ..." lu ln(' Clllhic lt

I'

II,

Tu rm wer rate. 1ll~/1.r.Salt form factor.lUI

-'S/\

units.

"r"\ ' rw

plll-'mla in ln whi(h dm~ dtstnbli lt'S.

Surfaet urea. m Z, 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.

I ..

t

\'I IIIIUl('

'-,

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..

'_.'J

Tillie "I which lht' h i ~ht'l>t dnlV; (11IK'tntr.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.

."-q uto 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 1 ' t'itlll' f ti l l' cure, the mitigation. or the pn...- nnon of M e t1iSt;L~(, . Bt'('illl'>(' all d m~s ('xhihit undt'simble d T('(1 s, such a. d ro ws iness, dryness o f the s mo u th, )!;;Lstruin lt-sti n.J irritation, 1lnw 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'rh~ tli,... In il.,, 1'i"1 (.. llo... .lt.... h

unl ,10...,. of a fil. ).n' lt tnulrullo..IIl"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", IRrfillt'(l W lL" Ihis d nl,g W sut't.'t..'ssfllll)", Q llin is t'l im inaf('(! slm"'!y am! it'(l at't..'lllllllb lt-s t> >nsi\,(-ly wnh n-pean-d d;uly ad mi nislration . 111t' allSV"t> ""l'i 10 \'t> 1 1I ~t' xh r 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)(> ,g l.'!l ofkn 10 ." .'hit'n' therapeutic s m't:'ts~ . Bo th cvclosponnc- and h d i ~o'(ill lIa\'(' a narrow therapeutic \\; m lo\\', hUI hl 't:;IIISf,' t')'{:II)SIX)rillt>is e1iminatt"f!Ill11t1I ' num- m pidly than d i ~()\i n . il hils to 1)(' ,gi\1.> mon- F 11 requently. O \)1odn is an ext reme exaruplc: it also h a. a !l am JW therupe-utic winduw hil i is t,lim inalt'(l wit hin minutes . TIl(' s 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. Btsid t> had oX)1odn 11t'i:'n ~\1.>11 o r ally, Ih is s. 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)ll1tS in ti lt" gil'"~ tminn-stinalfhuds . ~t Olllh i ll e , ~Wll orally. is also t1ts ln ~t'i:l substantia lly b efore (>n lt-ring th e gt'lle ral circulation, hu t fo r a reuson ut lt't.1illll, mltl d l'\"t'lopnwlll. Fo r txalTlple , 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 ss ad m inislr.\tioll llIay lit' sl1('I\1,'11 ill fa\1,lr o f a s 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 ..

Regimen 8

"ilhin 110., 1...ly "ntil

Therapeutic Failure

;t

i. n '...~ .... I, Will, n 'Kin.." A. 11"" "P""Iilli.lt' I" I,,",, ;tu ri>. ... ...Juah" u I" .. 4.'11.'(1 ;1.11!0IX'l! in this ~'Ct iOllllf the !XX)". 111is cha pt e r sllI:'l fieall)' dtfilws ! ('fIll S and idt' S('rillts 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't't l in lhe ga.stroinlestinal tml1 , fm m whilh 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'tfull)' ht'I\\'('t,u dnl~ ami IIIttaholile(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" Sf.'par,ltt'ly for kinetic d dat a lu he nlt'anin ~flli.

14

CHAPTE R2

DIFINITIDNS" h htlu ~h the- p rnn s ~ts of aleorption ami e-linunation l ift' dtM ti\'( and their II1tallillj., rip ~ 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"-"Sts follow. '

Absorptioni I.' III(' pm,.".",

f"rllo .', n ~ I,,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,

a d nl ~ illtrd\1l-"C:11Iar ly ensures that 1111 of till" d OM' enters ti ll' ~lIlt'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 F .. re-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 ~ lo cahza 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-

:\d lll i ll i ~h'ri ll !!

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.' tilll' p1w.,,' (I "'WI_ .. ila " .';,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;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(]lItous pha..... would ht, I mWI..: th us, 100 L I)f tilt" a1 1 1lt"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' 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-ldl'_n~',~ .

k _ Ra te of elimination Amovn t in body

10

til(' eii nuuatjou rate L't mstanl lIlity sim ply 1 ft1!1 ",-' lfll('t11 111(' jmctiOllfl1 m re {if dn,1!. w/JI onl!, ls Fo r e xample. sint't' Ih( halfli 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 F ...('(! ructional 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(' n' lIlai n i ll~ ill the body (NOose ) varies "'i tlJ tiun-. By (('ft,rt:'lll't. 10 Eq . 5. 'Frac tion

of dose A remaining in the body - Dose -

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 ( ':l imillalioll . Cleumue- (Iotal). dt'(Jot('t1 hy CT. , is that p ro p rtionalit y f'Ki m . Tlltl s, o

""'

", .. o'''el imino tion - CL Conce .,o,IiO". . o," e ""' , ,,

....

14

111(' uut ts o f eleanmce, like Iho ">(' o f [lo 01(( ' colunn- I)('r unit tune. Fu r example, if the w, d ('amn('(' \111ue is I l zhr , then al a concentratiou o f I IIlWl.. tilt' rate of dmg d illlina tiull 1. 'S, is I JlI ~/hr . Ortlillllrily, us the- conccut renon of 11 dm ~ i1wn '1 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

15

C omp arison o f Eqs . 14 and 1.'5 !('lIi1 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!O Wt"\'N , inu lin hlL\ a halflift 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 b seen th at d \l rill~ a small interva l of time, tit, eAm 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 . b olus ("(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 IA1, 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 tX;llllp lt, in tilt' eoL'it- uf tll' 'l)pllyllillt'. hy , .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 1 0 5()()-lllg lIost,. or 2()O mg. h;l~ 11('('11 ...Jiminalt'll fn uu Iht'! I(KI)'; 3lXl mg ha~ )'('t 1 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

INT RA-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. b olus 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 \ ', tstimafe... 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 tx.ullint't! in Chap. 19 . Distrihution Kiuet k-s.

RlNAl ClEARANCEElilll ina!iullCI('( 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 ,

""lllml lo this p llanllal'llkil1t'l k iuformutiou run iJ,t' ohtaillt'tl [roru analysis o f urinarv dat a. C analysis is lilt' t'l)JIl'!.'pl (If ",.,IIlJ f'!nlnlmY' . "\ l1 a l0l-~lI ll s 10 to lal ; ex t run-ual t..lt";tr;llil't' is dt 'h ' n uilll'l! hy d ilT l'T('!It't. 11 111s, extran-nal dear-lIlt't' is ( I - Je) . CI..

ESTIMATION OF PHARMACOKINETIC PARAMETERSTo apprr-cian- how lilt' p hannliue 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!Jtof tilt' dOl~ (';1Il ht ohtatncd from either excretion mit' or latin' cxcn-t ton data. TI lt' app r o priate nu-thods an ' dt'all wi th in Aplx'llflix I -H,t u(I Il , rt.....ltlat" " . .

n '"lralilM, li n M , Lola

Ki'n , in TaM .1-- 1. "

z: .... .gy~ ~ ~

1.0 0.5

e c 0.20

u0 0

0.1 0.05 0.02 04

C5E~~

c,

" 0.01

8

12

16

20

Hours

HK .3-4>. n... an M M",1 f"un 1... 1i. ,liWIli thmk I,k~ ...f II.., 1" 'rn'Tll n '",,,i,,i"lI: In h.. ..1......."..1 ~ ',.I tllTll".

n.,.1...,rl'li"l1. I.."",....r. th., It'n niruoJ h;Jflif, w~ II.., ..."... 1 h.."n) ".3 tl...n-f", e . il l. tI.. .-li miu "li,, " 1 ....lflif. 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 . an,l Trudo!a. G .A , l" fI" of.1ire a,Ml IIniel un hi"""".;I,,1>11;1,- of 111......,11) 111ne . C h n. I'h" rU l;U'11. nM'r " ; ,475--4'jll. I~~.)

~

'"~~

or

."ttI.

~

~

~

E

~

0.5 0.3 0

.ss c,

~

4Hours

8

12HI!:, t--S . "' '' li 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,/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 .~S!~"TO-'

_ 1HI ' ....1...1H.IfI'" ef 'onowl I. olld .c. A

_.",c30101372( U

COt of this d m~? fl. Btsllyah 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: Ab domen \,(' fSUS t hi~lJ . Clin. Endocnnol. J .5:40H- H 2, H~Jl ) examined the l' lTt" of s.e. illjl"u,.. we . O"d . ..... IB u~'>O. 1075 0.. F'Ion-o- 1. One co nsiderano n includes t!lC fadon; thai fd att' to both dlil'at" , and IS(' s...lft't)' of the dmg. that is. its phannal'U ' tlplamks and tU\k(llo~~)', Anotlll't l'u llsit!e t'a tion is 111\ 1 \' 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!tlI1. 1l- 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' va riah ]"s , lIlany of lilt" comple-x Inte-rn-lationships that ('xisl in 1:1..., are t1t'st n ~l 'tl. An, imal 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 b h lilt' variahh- ti me, with all that it connotes. and ot

Thercpecnc W IndowSod. ""'" To,,,,Jy Coeceeeceoo-se scoese ,elohon!>h t~

Ab>oon~

COO'

OWTH 5

55

till' elements of abscrpuou a mi tlispos ition ;1.. \\'111 ;L:.". ~ _ 0 o c

. '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 lm ,L.I. .. ....it l, .IT i i\ll l ll.., ,I. .. of K,K.1,W....r . J.: I.. 111(-,UlSl' of l' 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 -c f ic(:III'mil',,1 a.... In II W,l~IIf(' tilt' Individual i ..ay 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"lnmlt, Even wlu-u a Sll'r't'oSllt't:ific ,l\Say is tllIpln~ 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 p otent 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'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 ...... rfarin '

lO r ".-arf,ui" . ,I.. "''''1'1..\ ..l1i\il~U" ri,,~

'1"lM li ~

~-

642 0

e..,""ou~ .s~ ~

E

2

3

4

5

E~~ E "0

10075 50 25 0 0

c_~E

ce 1l~" ~

u ~ " ~

tI,, 1i"'1 ,Lty. II", ", lio..., "r rf;onn i_ . " ffiLn",,, lUll" ' t lil.., "r11,!lI....h n n-c i...'. (UU Mtj!,.. " n il "/ rnin

CONSIANT -iATE i EGlrW: NS

CHAPTH 6

1500

/ 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 halfllf... nN li".. i. til.. 'f"ndi" " C . 1320 ' (1 _ .. _ Q lnt) l l" ri"~ tI.., i " (,,.itll ' .."tI C 132l1 '.. - 0 .1. "',. ..

1000

lI...n''' (''-' ' TIlt- , ,.Ju., ,I

500

11,1. 1 mill - I ('Orn "l"",t!, In ;a h"tf 1. lift, uf 5.2 mill . (At4Jt 1 ("11 K...10'1' KW. .

"".1 W....tl...rJ,., R,C.: n... rJ...n nll ' l'o ~ i '1l'lk. of dcubl.. -charn ' I' A(d ",,~):

Ka'f'lr.

t',.c......". .\ lIn

A

KI" rl. C .

til., Williw, I'.A.

o

en,,

or I,,>lu> injo"C:-

o

40

80Minutes

120

160

lin" , in{" ..o.... a,.. I . I",I"I" ... 1i"" I.,. 4 ....-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 90

t-, From infusion

75~ ~

!,. 8~' 3.3 It.dfli,'t"5. II.. a,,,,,,,,,1 In 11 I u.~ ... ,, ;." ..1 will. II.. i" f"';'111I n;o r (m l"'l ..1,Lt.. I.."l lil" ). / ' In "l'p nl\i """" '1) 3 ,3 h.oIfli' " . 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,,, .... .. " 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 i1,,. of 10 "' II: a'KI a t'OIulanl-r infll, ion of 1,6 mWmin .r.. fur 611 min Itl lUI irKIi\id ll..J ~1I1'jt,,1..."',,1 e ' 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

7.300

C0N51ANTv, rER[GlMENS

CI-W'tH 6

Patient AHalt-lite Shorter than Expected

200

100

,

, ,, ,.

---

o~o

Patient B Half-life Equal to that Expected

." 2E

'" S 200,,

:

-. . ...

,, ., 100 ,,. ~. w,tiI..ftrr -rP",.j ~' 3.3 t..IrIn.."

1J\~

(1"'", !\ _

..,...,od> onplalll k

tI .. Ii

I. Onlv

....d

..........I IJ"'4'....'h .' AlMI C).

CHAPTE ~O

CONSTANl-AATl:

~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 v alues 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'lIItnt of th("ntpt'utit' l'llllt't'nt rat io lls, Ad minislt'rt't! extravecularly. however. with Iln- addilional absorption sttp, 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 PARAMETERSPharmucokhu-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' rtlt,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~lIttlll'll'ss, I;ow estimates of pilars lIlat'Ukillt'tit' jliirand half.lift'; ill this L st. tht' \,olt.lIlt' of distriliutfon is e,,,,k-ulah'tl kll0\\i T1!!: d ,> a 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 halflife l,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..

10 (C.. - C) during infusion

pl"tt...I",... tl..- , Itdini,,~ \'...t, .... of pL..\lIllt dn'Klu .,n'tll r" titltl (0) "'Pins! tiu...., il,,1.

5

o

C postmtuston

"f,,, " ' 'I'I"nK 11,,- infu.

21

0.5

0.2 0.1

o

2

4

6 8 Hours

10

12

CHAPT 0 H

C "C.. ' e - t ,

16

1'11('( '

\\11 t !le~' dilt;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> tha t ab u sorp nou is comph-te and , -irt ual ly instautuneous, o ral adm inistrutmn m il Ix' si111111 ~( I view o f accumulation , whi amount in the- h(l r.I~t r ate out, TIlt" ilnr.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 amou nt ill till' htlIt!fy high lhe2

0.5- 1 is Iiltl,' IWt"(! to coushk-r tilt" min or lIU l1uations. 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, ;c,.>/;t,ni''' in thi' ".J:.' 'nt h ti,",,; .. til II .. 1 "' 1 "t.." a .'''dt't!

CHAPTE R7

by olin' daily dm i ll~ is ("OUlIlt' rt't ! hy kim'fic \\ 'hen- tilt" opunnun rt WIIII' Jj lits 1;'''' r..t,... I..'tvo..." tv." ,L J., f" n,.... ~r.." '(I IlI. ,....\ 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, ThtIc.. I; n~ ,10..... " "lui"..ll" 1 it" . 1....J 1".li f. i. 1,4 Io rl. 1 1 tI,, ..",r.. Jo:1 ,"';,.1 .. y ... :.",..,, 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)

.1;.J. Ui" ~1. \I .. .. I'uri. S K.. II... I . i'.i ll ll~'. \I .A . "'KI SI....Itr. 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.... " '

0.3

t"'

.'

lIIl'l"U muLatit,,1. e li" . 1 nt""..l.i'>

' ~ ,., ~

'""""",, - -

"""""'*""appmo~

... ~ ~ d o ~ ..

, .,.,

.._

"'" N.:IV1 ,.." ,e III n""l"'n..lto .ha' ), " . , "'tl, tiM" "'11..1 ",ITI"n jl;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$. 4 Describe the cceseqceoces cl the levefsible IlOture 01 ~l 01 drug$ through men'tbra~,

So far ill tl.t honk. emphests has lx-en placed 01\ k jud irM~,,,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, (...rrior .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 m ' axinnnn. Furthermore, ill commOll wit h otln-r (. lr ritr-ml'i.liah 't! S)'SIt'IIIS, ~I II(.()S( !rdmport is n-asonably sj>t'(:i fle ami is inlrilutccl "~' ulliN slIll!olrahs. FI" WdmJ;ts IlIltran sport m il tl lt'n ' fo n ' b impeded hy lIlt"tahol it' inh ih itu r'i. v. t e

BLOOD flOWBlond . pt rfllS i n~ tissllts, 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 fItrfu 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\o lSS) 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 IXrfllSio ll, 11 01 IX"Olll'ah ilily. a.. sllO\\1l ill Fi.e;. k--t . This ptrfusiou 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 >tly thn m.e;h ti lt 1IIt'III Im lllt', a nd its rate- o f pas~.e;l' Increases . \\i lh illtn .l\ill .e; p erfusion. Thr- p.h~ .r"' .. lirnil... h tl" if n.. "' I> n... " ' Itl tlml{ i " .. ..,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".

Tissue

"'

III()VE MENT fHI1QUGH MfoYBiANES

orhe r larger polar com pounds than for ethanol or water, whkh results ill illS('ns ili\; ly tochanges 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-c omes ml e. lill1i li n~. At h i ~hl'r hlunt! flow rate-s. !ltl\\1" "er. membrane 1N.omahility !JI.'.. .."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

1.0

t-

Ribitol

o

1.0

Intestinal Blood Flow (mUmin/g tissue)

CHAl'TE P8

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 ilT t'n'ntl)", 50in,!!: nlt'mhr.ult' s. If t"t' n ' is a IlC 'r fusinll Iimilalioll , c!i\MIt'i"lioll (If lIlt'

CI-tAPTH 8

117

hu um l d m g am i di ffusion uf lin- unbound d r u lh mll ~h tilt' membran e mus t occu r so g raptdlythat ra tes of dd ht'l) and transport are t'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 F aster From lilt' (small) inhsti.w than [rmn th e slo tllad l. Bt"t'all sc' absorption is J;': rl' alt"f in the small inl lstim. tln - ran - of ~.t\ t ril' t'lllpt}in~ is a l"l llltmllin).t sh'P ill III(' SIW o f dOl ~ ahsorptiou. ('l1 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.lkt1l 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 tl' illlt'litlllt. lit litis Hog.m !. lilt' stu llIad l lIlay 1 , it'WI'l1 as a rt."[Xl'iitory o rga ll From \\~I kh >1;' 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 Itll~h . tltt illh'sti ll(' va ries ill its lltllltif" ' l' il (";/,1I 1...; ro" "'1' 1I1 f~,'ori ,,~ ;/, jI;rt'll!t'r pon....,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 ol,," it. J T.. HIlI"I'" S F.. l>itT.. rt. I ~ \\' .. suiOl". F..C:. ;01..1 s";,,t",~ a1.. "''1ltio.., I, ., ,, ill . it" .... ~nt 1t,Ol.t1t..;>t ~-.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-oc ecal j llll(:tinU. Snrf'K't an-a Ill" umt ItIIJ..'1h tit (n 'a.tpIiclillt I....... \0 110 .. It - .. I' "I1>1.. -..Ii1"',I_n. . ..... Ilolt" "",I~ 1,,1 , n ", ~ .It.. t ...h",'i>~ J_>tpIi. ..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 W t' 1I0! tln- rate.lilllililll?; ste p and Nit

s,;ltu ralt't l solnnon at til(' abso rp tion silt' l:ou ld Ix llI,u lllaillt' hriak Th' p"in" will, " n ..m i,,,lil..h tiK .. IIi'. 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 1 Ix' mo n - n lialllt. I lt' i n~ h-ss t1qx mlenl em a s i n~lt ' e-vent am i o n food. 0 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 IM I' ll and a~t'l lioll . In Slid . ( " (.\("S. V;.lslri( t'lll pl~i nl?: hax litt l( (,!T('11 011 lih 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' lstri11";1.111"'1n in dish'iburionb . 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 ofdislfibulion is known ,

5 . Cokokne the fraction of drug in the body rho! is:

a unbound b In the eXlroceilulor flUidsc. 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 plmmo6 . 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 \lr,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 kimlit u lll,i d,r. lliollS ;1m! c'lId, \\ill. I'e!"ilihrillll i 1'(11 11'('1''''

RATE Of DISTRIBUTIONDi, 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!; \\111 tiuu-. 1137

131

CHAPIU 10

IlIdlll ll'(l an- 1I1lin 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,.. - ""',...-_

..,

,~,,""r"""

.

~.....

II

,. simanon is eqmvalent 10 stu l). pill ~ a coustant -mn- inlntH'lIuus (i.v.) infusion o f t.lmg: al ~hatl~ sta tc'. Ht't"i,1I (C ha p . 7) Ihal till' .m lllllnl in 111I' IlIMly (nr pl'Lsma l'tlll('t' nim tio n ) tlu-n f.ul~ c'xpol1(,lltially hy olle half (';ldl hllif-Iift" HI-call also tha t tilt' Imctionn l rate of eliminatiou is the- ehmtnanon nth' (1J1l..taut k, a m i ; LS ' , = Ilk,. it r(JlIll\~~ tlrat :

5

'" "000

.~

4

A.3

~ ;s: 2.;;; "000~ ~

~

, , ,"

----,---

t,

.'34

, , ,

F1!1t. 23-2. [''''..... ~rt7I >h . n .., p'.. .t Un' illt....-~ Ii,..,,":-' illo lill.. .. t....., (..I am_ l .hl"in.odi.." ,. n .. nplo ~ hlo........1 ;AI .. I i"I..,1 r..t.. ",main. nn t ....,'!:' ..!. Th . 10'1'" i. tI.. '''';11:' '''''' I" n........ ".t. . ,'l .. It ,. 1......... .. "'1>1'. n .., r-oo! " ,I...-n"ll- " ilh _ tin ......1..'fI ( . 1 am",,') illp" t to t.""pIo-t..~ 1"' .......1. n... tl. .. t i"r K l"tJ"....n tl.ol ..l ..... fin.t..."..I.,. tlind .

.i,..

llollion ~I .. I

O tMo1,,< ;klm;n i. r"i"n ,,( '1kk1in a1 ra ( IIM Illliblllt) ( ) ;,....i: n"'I" ~ "'I" 'ri""'''1 (O J. ' ",.,1, 1"1"'..I""hil..l 1 , n...,., 11:372.--377. IY';'I U

ill "'.. "

el",

o

o

.,8

CH....PTH23

The-n- is a It'ndt ' IW\' til (.o lld udc tha t ('11:\ '111( ' X is indut,"tl wh t' n ',ls ('1lz\11W r is 1I0t . ' At1ually. (nz:."IllI Y m~y han" bl'('11 more iml;I{'t'(lthan ('110111(' X. Thi s l"om!itio ll is shown in Fi ~. 2. -12 , :\ ' t hnu~h induction is \irt ua lly instantuneons 0 11 adlllill isl('rill~ plwlloharhila l. 1 l ilt' ('!l Z)ll1t 'S !la\(O ilTt'rt'llt tu rnover churactcn sncs . CCJIIitlial}~ s~~t ..", ill whicll dm" is f"'l~'"'~' lnu~,r.. rred lll'!'"" 11 ..."'ip" m M lt, " ..",tmu M ( j fnom hlt..l lu tliaI)......I.. . Oru" ill d..l j,. ..rnJ lu tl... 1)'StO"fl' al noll' V".. ' C" .. and 'ah . i' n I" n .... II" ,he ,....ly ;i s. \ ' . C (O). :\ mon- ap lwalillg pproa is 10 reston- tilt.' ch amount ill lilt" Ixxl\' at tilt' eml tlf diith-s is to tilt' \" alut' tha i would haw occum-d l...d tilt'1 lD. T ilt, suhS('(lllt'nt dtsc siou Is largely n-stricn-d to this d ialysis modality. us

Dialysh; Oearanc.In CAPD, dialysis clearance. CI." ,. is most frt'(lllt'IlII}' expressed .IS the amount of a dnlg o r sub sta nce n -c n-d in till' drained dial)'satt' n-lat ive to th e Aue du ring lilt, dwell ttme. ove r . afll'r atlminislm tin n by any rou te. A Il 'lltl~(JllS to ECI ' 4 and with tilt' s\lhM'ripl PC 1II('aning peritoneal cavity.

CL"" ... Cee Vee f~ C d,

17

when' \'1"{: is the lll

Ii,m of .lmK

Ii, ,, ... ",,11.' ,,,

ti"" rn .....itl, " ..Ii'lri l,,, "b.,""" "" Ii ...,

,,,,h . Iu d ClI...I,;,lf "f 1I1l 1i,1 ,lum illlli;dl.-in II.. lu~ " .... "-"",,,...J 1>:- , IW~ ...i . A nlt'l-of, .~in ...t. of (r;Mi io" Ic "" ...... I,, ,,1>1;.

Table 24-3. Representative Substances for Which Extracorporeal Methods (Hemodialysis, Hemofiltratian, and H.moperfusion) May Be of Potential Va lue In Treating Severe Intoxication"Acetaminophen Aminoglycosides Amobar bilol Diozepom

Ethanol

ButoborbuolBromide ion

Ethchlarvynol Ethylene glvcolGlu tethimide

Corbomczepine

Chloral hydrate

[Inchloroihonol]

lithium Methanol

fvlelhyprylon P araquat Pentobarbital Procmnornide Salicylic ocid SecobarbitalTheophylline

"C........ U .. fO/lor>ciplel 01 0"'''01 r""coIogy 2r>d ed , ~..,... Pr e\>. New YO/_, 1990. PI'. 50-55 Pond, SM. : E.=,poteol'ed-"q..el in !heIreotmeftp 01po;~ pot"'... IV'edJ M .. 154017---622. 1991

...STUDY PROBLEMS(Answe rs to

Study

Problems are in A ppendix Il.J

1. Dd illl'

t1ial~"!i i s . ('xlral'o rpon 'al dialysi s, h( II1()( l ial~"' i s . lu-mofilt r ation. l'l llltin uous amImtltory pl.-nte ml',,1 dialysis. dia lysis cleanmce-. di alp A dial~ '"I.t r d fidt'l\t" , and din im l f.

tlial~I. ahility of it

d rug.

2. a. Complete Tabh- 24--4 by l'sl i lllat i ll~ IIllho\l ml and total di alysis e!"' ilr ,lII t 't ' value s . th e r atio o f Ilalr-lin's 1)('lw('('1\ alld d ll lill~ d i;J )'sis In'iltlllt'lIts, am i the- half-lif.. IX't\\ '("('1l di,J)"Ji, is treat ments for (,Ia~c n 'nal tli",a.\t p"lit'n ls 1II11 L rw tin~ h. llIofilt ratio:m (p m" k' J11 ao: Laph '(l fmm data ill GLttmua.. U. "': ri~lma. D .R . K lut /~ u.. Iu d . T .II . St:huuL.rt , II . Gk Jt kfltr. \\".~I.. ;l1l.1 ~I all ll. II .: Ph ann.tIiIM.' An l' nt. t"''1'l1..Iia. H.......1. S K~ r. : ) 19\7. W~,,r. J.: 11laf1Il;l(o LiIM 1it.... f"r 11M 11u n 'la' , .....ltit.'OIl St;'''IJtht . l .a'..~... hr I.... T... ~ IlM.mic. 199- , 1 \\.... .'. HC.. anti .\IAi!>;....,. II I .: I',n...tal"""" 1 ...1 "111..,,1..r .In,I:''' Clin . I'h...nn ill'l.LiIM'i . .... 23:2.').1-;266. 199'2. \\,lIilllt- I'.. ...,.. 1 T .. II .: 11,...rm... ...Lin.1K'" R,"J~ulatu~,- 1 mlll'lriaJ ...t"IMlcmic I'c'o l" ":-IiH "li. Ul flll:" ,,, ,,1 11M 11..tnu..... nlit.'OIl St;' 1l'l"li Sor. Xo. 3.11. :",..... \url . \1 " R'l1 ..1 )).:111r. l!J-W Wcllin!t. I',G. ami T.. -. F.I. S.: 11Ian H ILi' Kt ,lt' ic.. of Canli....'a'l' llar. ( A'lIlral :"""'''.1' S\'i n-m, ami Antimic:ruhia l Dn 'l.... l~ l1 l(l.lt l . . Hun ll St..iclv uf C'" ;uIIt. C. 1.." ..1)11' \." . W,J.: ()t ~ "'1:'''M'11 .It-si~ l . Ih... n 'l n ol. TIMr. J;",I U - IM . 19\1. c....lm;ul. I ~S IKI G, IIIUII . ,\ ,: TI", 11un'lat.uke'Oll 8 h "f TIM lllic-s. \" .1. I. 'oIh r.q'll tAl- :'\...... \'"n.. .\h ( ;r......-II ill. 199'2.

...H e ilmenn. K .: l1Wnlpt'u l k SySlt"1I1S. Ralt,CulItn~Wt;1 D nl l( o.lh' I)~ CfM :t -pt anti "

l).", t"!.

up llw nl . 21MI Ht,\,. Eel S t"4' 'fo rk . Th it'm.'"

Slr.lltun. 19o'l.1 .Ulitmm . iUltl l>(kf'flll. C.: 1'han1 1,kino1k 1a( ul)t im i!loat it~ o f au lk-.... '"r tht"r.il~ ' e lin. K rtlMl lI;K'UkiIll't ., 2 1::213-23 1. 1991.

J.,

" rplic." ,," . Clill. 1'1':lr" 'iK,.l.::illtl.. .di lI:3'l7-4Ul . 1 9-~. \\il:ww,. K.: St.,-n Lth'( l (lifTt' n m, "I Iu d fllK (Ii'l' I"l'Iilion in tnau. C lin. Ph an".tt..-.l.i IM1..f,t:l 1,;9-2f ~2 .

(.J

19-\j.I,

n

0.1. nit"

" IJ :I .i9-Ut1, 1 51. 9'

, Om!:

1;..

5\"51.. 11

PIlM1' >a'

(~nM M;,

Kalc ,.,~t, \\' " ( ~ II:'(It", . \ \ '. 11 . itllli '''-Il:a rwa.l. Ill'.: Etlmk Di fTo ut., "'l ill Rt....1 icH.' 10 I>fIllC' .

and Xt-nt Jl Iic JC k~ .

:'\t"'o'. \nr k. ."-lan R. u,

' 1M.Lin, J. II . c... dMito, () ,M aJl(I DujiOC.rn. D .E.: Plu b-in hill. li ll~ a. a IMima.,"drtt"nninan l o( t1w- "mio.:a! pb;tmll M:'l> in til, tkitr1y. 111t rallt -ut k (u",i'~'ratioll ' 1'",11 II eli" , 1'IlOI n niK, ,ki' It-t. , 21:262--273, IWI. Knll,,r. It. alltl D.twr. I'.: F. I>l1 t lnJ ~ 11 ,, -1...111>' Ii'llll >In, 1 it. 11I':" ihl. f'li ni' ~11 illlpli("ltlinn'l ' C lill. l1 ,a n n;l(ukil... I.. 2 1:, ().....N I. IIIIJI . S o rlJJall. T.R : Pl. arma(" kindi( a.' llot 'l.1S o f alllitl'1Jn'~\ill1 l trr-atnn-nt in tI ll" t'l' '' 'rl~'' I' rUlot ~ (II " .. p,-y 'pllilrlJJ'K" '- Hiol. I'syd Jialf)'. d" l i :329-.144. 19'J4 Rihd,,1.\ \ '.: r",nllll"li nd k., : 1'1,..n n....llkilltlk-s ' (If D m ",\ in II,, EI.it rly. Telfor dPn-se, IWt9 . W alLK.. S . ~l . alll i \ tr1" "I'l.k. It K.: l'Ia.'lllla pn.. It'in hi", IiIlK o f Jim"" ill thl d (itrly. e lin. I't I;&nllilt"kiI1t . 12:4 1-';'2. 1Wt7. 1 W(lI.. UIt",\f, K.: Dm~ alltl tiM liw r. Pa rt III : "~('ill~ "f tlK li\ 't'I ilIM I ti lt n...I:,I..>l I\1II ,,( dnl~ . Bil'llol.a n ll, I>nllt l>i'lllot l'\. 13 ,31 1-.320 .I~.

Di..........lk-nIK1 t. W .M .. A"MIt,fT G R. M" rri :w,n . (;. . Golpt'r, T ~"- . I'u lliam . J. Wnlf'IC ltl. ~1.. il1Itl Sin~r. I.: DnlJ;t pl't"lCfil>injitin n na! fa.ilul't';

IiM ....-. Xtw a. Ynrk. Sprill~, r .\tr1;,J.:. IW :2. .\Id ...'an. :\.J.. a mi .\ l n~;u . I>.J.: Clnucal phar. IIIII~i, ll rat i< "I' . Clin. Phar1ll.K'l',killt1:.. Z-l :.'36:2~179. I~J.1 , W iIlWm. ar. , Beater. D C . ;IIKI .\Ionw nti. J. 1,,I; k): DOle; ., .. In,inh lrat i< m ill Di.........w " Stal t'"> , ~_. York .\lan" I IJ. 'kl lr. 19'1-~. \\'on. ma n. P. and G r.lh am. .\I.A, (t'tk): l'harnJiIIl'l'lki....-ti(-s ;lrMl ('arM"r C)"'IIMJtkr-~'. . ICano.." r SOl "''':''' Se-r.. \ '01. 17.) Cold Sprin~ lI a" M . X'I. CoM Sprin( Il am o r l..J.h()r.. . t~ >r Pn -w, 1993.I nt l" rari in~ Dru(\ 1I"'l'h'Il. P.D.: Dnl( Inh' rillli i\. m , ' 19-....'>. \\'tllilll:. I'.G .: Inl..r.....1'on.. "ff''tiin( d nl K at.s...rpti on. e lin. I'han llililu kimi. 9 :4()..f...4.14 . W' MII!. .\1.: 11Iam lac..,\..i ' M d n !!!: inlt'rilll tions in 1:ic itJl..~t hl1 i( p rillli i- 07 . 199 1. 1 .\Io n itu ri n ( Rurtnn. .\I.E .. \a..~ ko . .\I. R.. itIMI Br atl"f. D ,C.: C , mparL'iOll o f tlm( dU~inl: nK1IMXk. Chll. ... J'IldOllilll"(,h l...t.. I t),) -J':'. 19- ..) \' ..:...Ia ":imll"'. \ I.A. '1"'11I( . l~ 'I. G II~id nJo. J-. Jr . alKI ":rad jan . \\'oO' .: lf alK!lMIIJl;ol .' pp!it'd

11llInis. P.J. alMl Stan.ki. D.R .: t-1'an nillu ki l....t iru ~ \ It't.m. :'! nm~ l nte-... .1,. fi,.. ;-J;,. . 199-1 . 1 I'an ~. l.:.S.: " W\-M....- of IIlC" bhlllK" " 1Ilt11("'l.. Jl'Iwn ll..,.LIM"t.. Bi..I'......m.. IJ:fi,."l-Hi:2. .19'1.'). Tu""" c-r {'.ol1o"p hR. "\(; ~lo.

;tlad

" . and Sl",. G.: Tllnll....., . / n I>n l)t T r.M't' Kilwt in. W061d u m. M.... oW....

.1011. Il:lffi.SI ,jp~. R..' . and CL . R.f:.: T rMT" ~I .-t tx. b u\ fflr III \'~u Ki 1 1('S: 11lt'll ,~, ;llld .. ,-.plll.'a\

tium , St.... Yurl.

('". I..-mit Pn ",,,, 1",,2.

rn, d m~ tl.!i\'I"rv: An tia'ldlluali("!i , Il.-hl..d ....... and cnn h..\'a~' , Ltr 'M i \l ' dm~ . :t .\ t..... J) m~ l J.];w ry It,..... 6 :.'j,.1 -IU I, I YO; , ' .J..I " ;In KI)'i,\ III1l. J.M . VlIn U II!o:t'll. G., ,IIM Hu'W..... I J I' ,T .: 1>. ....-(10' .'"1..-111 r' ,an n. 'oldn. lic':I.. P1" m ll.K n il" " ZI :;;_ lflO. I~l. ulki1U ti("'\

0 0_ M TinW' 1>t-pc-mknciM. OO I...hnu lm'. G ., .IIM KoLoUIl:'" P.M.: Ti mt,-< I Jt.. p' -IM 'IM;)' ill lht p l,a n IlAlold no'!i("\ a m i Ili'!k ' ... ...ili.. n nf tim ,., . I" T upk "lo ill I'I...rm....x-uti a cu mulative amount excn-ted. n i l' amou nt C'X{'f(!t'{! ill e ach tune interval is the pnxlud nd of \1I11II1IC of mint' c'(,llc"l1t'i! allt! l'(mt... n lralioll. to. ~ . the amount ill Sample I is J20 III L tum-s 13.1 J.I Wml. or If) III g~ the refon-, tl u- a\"t' ra~l' rat e of (' Xl'n'tio ll ""cr th e firlOt 2 1. ,. 1'l('r1txl is S mgtllr. n it' cum ula tive amount escn-ted up 10 '1II)' time is the sum uf all d nJ~ excreted tip 10 Ih'lt tune. Hy 24 hr. 11ll" l'ullllllativt' amoun t excreted is 39. 1 m~, ami siul 't' 37.2 1Il ~ was l'xen'h-t1 in tilt' first 12 hr ami u nly anot her 1.9 Ill~ IM'r the next J2 hr. 39. 1 m~ approxnnates the ultimat e amount of d m~ excreted.dnl~.

Excn-non rate data are IK't'l.L; ~\"(' Il ill Chap. 3 , namely, Ihe mensured u rtuary excretion rate rcfh-cts the an'mgt' plasma conce-nt ration du rtng the l't)l!ection interval . Formal pmof o f til(' oh'>('I'Ya lion of elimination half-life is nol dffficnlt 10 dt'rin-. Usinv; El l. 21 o f C hap. 3 ,Excret ion ro te -

Cl l/ ' C

If DoS( (' -AI is su hsti tllh'tl fllr C . "

,.111.

"'1 . Uri. . D... OIl"'Ine4 n_.I..... I. .. . . .I De_" Dn.wO8So! "''''TlON

m"'IMENlOI Dill'"

""'" 01 2 3 4 5 6

coacro-, h'

_a

.,,,'" a .....~,

l.N:HilNC,lD 0IIllGN

a

CQNClNllATlON

oe-e

1>NCJU'.lf EXCRETED

N TI'.If M!VY.....

,,,,

ElC.l:fTlON

1Iog.' '''lJ

8- 12 12-2 4

0 -2 2.... 4- -8

'"160

..-,8 45 28Il

""""

>NOM

eomo

...

120 180 80 340 178 950

133 50 63 10 18 2

90 56 3432

19

0 ,16

0.8

16 0 25 ,0 30 ,6 34 0 372 39,1

'" 0

""""'. eomc&

~ ,o

39 1 231 14 I 8551

'"

19

4"

.,.Excretion rete a lltl l a ki ll ~ lo~:a ri l l ll lls

9:E ' Dose . e _ .1:1 V

2

lnlexc retion rote} = In

r~ .Dose}- !: . ,

3

'1111" slope- of tln- curve- is - I.:. the- m it- (''Ollsta n t for ehminution o f t1m ~ by lui n mlt-s . E\1.'n if n -ual 1'X('rd iol1 wi-re tlllly a small Fraction of tot al dm ~ r-lnninatiou. tIl(' ('x('n 'tiun n il" wouk] still dl'( ,lin(' \\;,h ti UlC' in plirall..1 wit h coucentratton. Concentration is tlw dri,; n~ (on" for re-nal t'x('rd io ll: a... concent rat ion declim-s, so do!.s mit' o f cccrenon. In prad kt', 11Il ('trtai ll l~ of ('o mpll"II' bluddcr t'mpl)ill~ and need to (''011('(1 urine O\'t"r short tntr-rvuls, rdati\"( to tilt' ('lim illati n ll half-lif, fir tht' dnJ~. pUS(' limitatiollS Oil tht' '1IIaht)' of ewn-nou m it ' dalli. \\l wl1 complete mint' n"" 39.1 Ul ~ CiUI II('taken til h.. an (-slim,d ,, of tilt' hJl:a1 amount of t1n l~ til ht (""crt,It...1U1KIIaflJ.:l'tl (iV..). ' Halr thts amount (app m u malt't,. 20 m~l is e xcreted by 2.6 hr t'

h ut Jiin(.. ,, - - "" 0 , and \' , k\l'n hy

= C L , tht, amount t' uTdt"tl hy

Ae

_ el R Dose CL

9

1 Ao{ ~ - .... 1 - . -',

10

.,.11111.~ ,it

E STWATlQN Of Eij\.o\NATlON HAlHn

f~

Ui lNE DAT A

11

and l akin~ logarith ms

InlAe", -

Ae(~ 1 =

In Ae" - k ,~w a sl rai ~ht

aM milngilrithmik. \\ 111'11 ( ;L~ i.. m ost fTt"lI"tnll)' l ilt' t~d.~') ah loCl'l). 'tin n is a mo rt' rapid p TtIt'C 'ss than t,liminatinll (ka > k ), tht' value of lea . t is always ~f('lltt' r than k . t , and In-nee (. - l ./ :lpp n l~

c

40;

;;U

~

~

;; 200~

-c

E

0 06

12Hours

18

24

('< 1I1t1'nl r.diun

Flit. 1>-2. .'tf'" lUI t v. h..lllt ,...... . thr ,>tull,,", (lu k ("n ) ."dll"~ 100;11,111"... 11... G", -",,,,,,..,,I (t".Ior....1..., 'ro). p n " lu(1 nf lim., ..lid

10

20

(~""~'f\l ndic",.

Ih'...1>-1

n .. .."... 1...,......1 II... t...1

n_ Iu .. pt...l 1ll,,1 .10..:1" will> 1 ....~lIl 11i"R lim.. i.

much 1tfr"I,r 11. It... fint ''''' '' '''"111 Umr ( 'U...... II...., " ... It... n.Il'f'flI...tionlim.. ( 'U....... I). .. fn " " Tal"

o!-_-~~==~ o

o

6

18

24

...IIt 'llli'l l ('u (ffi d ,'uh

AWENDIX I-D

wILt'n' }.= is tl\(' rat e constan t of till" terminal dl't--.ty of the plasma dnl~ conce ntra nou. \\11I'n th,' r-u tin- ('l:ll\{'(' n lmti oll -t i nw proflk- ca n ht' 1!f"lOU S

w.1>N ~5CltNCf

"""'AN N'VlllW

""1/'II I + 1 ,,/2 II I + l ila

bol..s doseConSlOnl-lOIe

5 -2....~~ 13~~

0

onlrove ruJ( tli.l rihu lt1 "" ""'11: pL...n... (.....t,,"'.. . Ih. ...Il'lil't"lI"L IInitL " " h itlt rL...II... (. , 01" " .. ., . ' l ) .." .11 R" u&i.... t ,.of 1I hc..1y ...\dl'r (Y "ll" - " ,,). F.tluilihril"n i' .....j.~.....J ..i .... " "I..,,,,.. I .u ...'t"nlro&liurn I. lf' ' ol" in 110.. 110 "I-'" IU't" I.... t...."..J .n1KT" l r. ti< ill I.... d on... 'I_~ ;on ' (u,.. 1i.. '" urtI... ;offillil;'" of .In'l:: 110.. " ,I" laI" "" in It - JP"'-" Iu ...bit'" It..