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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""1111111I11111I1111111111: 11111111 ALOS- 706- NZWP

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¥'$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"rr" "'1l'

Iht- /'"hlu/l('(:rt'It't! drug reabsorbe d ill tilt" renal tu bu lc, no units.

\ l ichal.'lis·\le ule n constant. t'Xpres sed in te rms or lot al plasma concentranon. mgIL or p \ l .

Kp

110 units.

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. Fract ion or ..d min i..lt' r,,1do!>(' or dnl ~ that l'nh'f'!i ti ll' J.:t' llt' mlcir-

F

U rillal)' escn-non rail." constant.

11f - I ,

/;

~all ,

Jm

AS\lx1ali oll co nstant for tilt' biml · i n~ of dr ug 10 prot ei n. 11 1J1olt' ,

ft·

Rat io (If unl .Jl.lIltl and toral dm ~ ('OI.IK,'n t r,dion~ in plasma. no umrs .

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.

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.~·.

v

1.1. :\ unilk" .. nu mbe-r. :-':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,

I 'r

PIa.~lIla

\ 're

\"OIIlIlW of dial)"Satt'"ithin lilt' pC'rilulJ(·ll! cavi ty, L.

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

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¢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':;n

ArneIOOfO!oon 01 ~ cc-dcc fo;~

"'" "'"

0e 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 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;....1;\1' i, ...-I,i,"\.,,1

''''In' 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>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 do ...agt· n ' ;IlH"1l d dOlI{ lIla~' p rtl\'t" tberape-eric ill 'iOIIW patients. itw ff......1i\l.· ill otlH.·n . am i tovic ill ..till or hers The Iwt....1 to adjust the (1oY.~(' «'; IIH'II of a dru~ for an indi\;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 !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' 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-' 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;C'l.'IiIU ' in plasma roncent r at ton dunng tbe diminal io ll ph a.o;t;, ca n II(' d mralopC' 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':\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'(' 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 ( ':

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 !('lIi';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 ; 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. n... an MM",1 f"un 1... 1i. ,liWpt ·aft'tll)· I llft lll~hoU I Ilu- hook. To 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."Ili 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;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 . 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" rUl;U'11. nM'r " ; ,475--4'jll. I~~.)

~

s

'" ~

0

~

~ ~

E

."ttI.

or

~

~

"'I:

,,"';llO

§.

.~

c1,., lIi,,.· " ,. . .1 r~>i, 1 .. ~ ..·n tI... ,,,h it.., "" ' 1'1 ' di. ...>1""11 ill

6

c

T" ., lal.l 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 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, 110." ".It' th e om' with the highest hioavai lahil it>·, th ai is, tilt' on..' hOtl 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'd , k "'"~nglo _ ., _ ...... I,." I>oc "' ''''

COt.. "'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 - 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. 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>oh 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 lheormocogeneliu-odl 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!lI

1500

....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 ~ ~ ~

~

!,. 8~' 3.3 It.df·li,'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.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' 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 ,,.. .""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' jliira"'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,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~' dilt 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 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 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" IXIa re- fundamental I'd atiomhi ps; Ilw)" show ho-v til(" a\·e rJ.~l> amou nt ill till' htl

Ccrdcce lor com.fQnl-fO!e odmmis/l'ollOn ond/or lhorHe241'1f

......

~","""

............ _

0.5- 1 ......

~.

C1a....d,rwl' l1equile$cOleful conlfal. once fQxl('Iy ;$ peodcced drugcooceeeosce cod IQxic'lydeclu-.e ~

..-.. ............. _"'0 io6 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 h r 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, ;c,.>/;t,ni'''· in thi' ".J:.' 'nt h ti,",,; ;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:.· 1j"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 Ilw"'" 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: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 ,·.." ,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't bra~,

So far ill tl.t· honk. emphests has lx-en placed 01\ k jud i" •.

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 IlIltran 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.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.'.. .."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)", 50l;·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" ' 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 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,rplit., ,,( .....i .. ' l1..·" (15C1O "'K) lnriuh'r" ..1onoll)'; lI. 22.~. '..r-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.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' 1"·n,,,·..l ,ih ~ r..tt··!i"' i",t1 (c • ,\ ). "....I " f tI..· t1m~ I"" \"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.· , ",,'it1'·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,

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..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