Clinical Pharmacokinetics: Concepts and Applications

602 Pages·1995·58.69 MB·English

by  Malcolm Rowland

Clinical Pharmacak inet ics
Concepts and Application s
thirdedition
MALCOlM ROWlAND, Ph.D.
DepomnenrofPhormocy
UniversityofIv\oncne$ler
fvlonchester, England
THOMASN. TOZER, Ph.D.
School ofPbcrmocv
UniversityofCalifornia
SanFrancisco, Cclnormc
A Leu .v.... Febiger Book
.e1~
LIpPINCOTT WILLIAMS&WILKINS
• AWollenKluwefCompany
Philadelphia • Ballimore • NewYork • london
BuenosAires • HongKong . Sydney • Tokyo
f:.w.:uIIH'f:.I.,,,,,!)""'..l H<u.lll"
11tlO-It'/>f'U"Udll.;.[I/.-n Frmu.·#"!I-:litu, I.L<{;i :'>tnl<1
'.....1....·'''',.,.u.....lR"... u.urw.·Ft>¥'$J1h
f'n:>J«t/-:.111"" J(oh."lJ .1I('1tt,·
CopyrightC I99S
lW ~r,lI..m.l!<~'iu.,;...
HO~·01 ~.....
Pt"l.Jdrh'"lm yInft..1'1101'>-:1021 l''!>A
Allri¢lt~re....'rve·d Thi~h<....i.~I'rul~-..:1•..JI')'cnpyril(ht,...." p;ln (>tlhi~h••oklIu)'I... n.·pr"du...·tI in"ny
'..rm nrtl)'..n)'rnt~"Il-~.indudmjtph'lIu':OPyinll.0' ulllll.et.lhy ~n)'infumulion """'-"11<' ~n<.I1'1.1,...·,..,,1~)·",.-nl
.....i1huul....Titl.-npemli.,~i"n(rum lho.-n,p\.-rixh!......I'll·r
An'Ur~l.. inlJiGlli(>n~.~.h'ff'>t"ll.·oI<.1i<...~.~ooJ<"..;I!lt' ·hnluk-"furdrull"an.'pt<"i<.k'<iin lhi~ho...ol..hUIr( i.~
pr...~ihl..lht.1'nuy.-f'l:In!lt".Tho.'...·:l<k>fi~UrwnllO ·it.....'lhe.-p;ld.,.:.lJC"infun1l.llKlf1wI"..rII... nunub'1u...."
(lrlho.-mnli<.~IIIl"'~rnt'1l1K>nnJ.
I'firllcdin11M:'l:nit..-dSl"l..,..,rlAnlt"fit'<l
fiN h.l.".... 1....'
UbnryorCAm~Cata",-""lnK-ln·Puhllcadon Dala
Itu.....boo.1t-f.l.kolm,
Oini<'<I1Plul'l1U(,<okiOt1o:('tIfl{"C'flI-' "00arrl""lion,I Makohn
Ko.....'.f.l.n<l.Th.......~S Tozn".- .W ......
p, em,
MAL.....'t Fd ,jll<>fB.."k.~
Indu<1o:-!<hihli<'Ilf'lphi<.·..1n..rl·n..I'll~"ooIndo-·".
ISUS ().(1Mj-(J7i(~·O
1 Plunruc"killt1it'!o l Cho(.-nKJlhlT~J')·, TOIt·r.l1K1flU'S,
n.nne.
lusU.t 1.Plunrun okllw:iio l.Im..1lTh<.T..p)· QV.\IillSK;k 1....,1-11
k.\1~1I.~.R6K ,~
61".7_klO
')~L\L,()LC
fur lihr~rr..tCAIOIlft"'"
Iht-/'"hlu/l<t'f'J1><111'......1<.",.ory.tJi,rr1'-'Irw.·..lho-'·''''.I'tlNblh.."·Ite".U,.,.i'1.0,·'"I".....>U••I"..1I•."..11/lhory-'1><'/1'ill
'l</" 'f1t'1,lll'"f,-rl<"Jit.1'''IX.Iht,·"1111...pl.u....1to _ d.•' ,''''II... (lm"lRt'm",,',~(.1Iht·fiNo(>(>"rr""'1l'
9 10
PREFACE
PURPOSE 01 TIXT
The rhinl l"tlitioll. in kt't'pill~ wtth tilt' fiot hm ("l;lilions. isa pnnu-r in pharmacokinetics
\\ithan t'llIph;l~is011 clhucnlapplications.111t'Ix)okshould hl' usefultoilnystudent.pmc·
tulom-r.or rt'sl'ard lt'rWilliisinf('rt'slt'()ort'llga~("llin til('dt·"dopllll'ut,e-....uluutkrn.orII!\('
of nu-dn-im-s.SIl('h !Wn;OIlS illdlldl'phannac1sts.physicians.veterinarians. pharmaccuucal
scn-nttsts. Im:ieolo)..,'isls, al1al~1i{Mu1chemists, luochennsts.and d ink'al chenusts. It is an in
troductorytextamitln-n-fon-pn'slllllt'Sthattilt'n-aderIm."littll'or not':qx'nt'IIl'('Of knowl
('(I~t· ill lilt, an-a. Previous ('xposnn' 10 certain aspects of physioloK\' and pharmacclogy
would ht' 11I·lp(1I1,hilt it is 1101('Sst·utia!.SOIllt' kllowlt'(I~(·ofcalculus isalso dt'Sirab!e.
Ourintent h to ln-lptilt'n-aderlenrn to applyplranuacokincncs intherape-utics.Tothis
r-nd.WI' I'lIlplJit\ill' {,(lIll,('pts tlln)ll~h problemsolving \\ith only til('essence of requtred
marlu-nuutcs. In tllis respect. til('hookisa pro~r.lInm{'(IIt'aminv;text.AIthe bt";ll11in~of
I';u:h d lapll'r, ohjt'(:liH's art' !-pH'n 10 itll'lltif)"lilt' saln-nt points 10 be learned.To further
aid in !e;ln-illl-: tln-man-rial. examples art' \\urkt'(!oul in delailin tilt' text, At tilt' {'ud of
t·ad.chapter,t'Wl'pttilt'first.then-an'problemsthiltallo.....I!l1'readertov;r...'ptilt'(,(JJl{"pts
oftilt'chapn-r,IlldIn lnukl man-rial ¢H'n illpreviouschapn-rs.nit' un!t'roftht,prob
1)1\
k-msin I'a('h cliapter n·III'(1s cousuh-ratiou of both t1HIi(1111)'and how WI·I\tlu-problems
apply tn chapterprinciples.TIlt'questionsstart with thelessdiflitultOIl('S and thosethai
t·.llplmsi...x- tlu-principh-s.
ORGANIZATION AND CONIINT
Asin tilt's('('(md t'(lilioll,11\1' I)(M)kist!idt!('(1into fiv('St,'<.1inllS:AbsUlVlionand Disl'll,).'iitinl\
Kim'lil'S.Tll{'raj'll,'lItil' Hl'¢Illt'nS, I'hysinlo¢ cCOII('('plsand Knwttcs.Indhitluali...atiou.ami
SI'!l'(1t,!Tnpil'S.Tlmst' \\isllinl-:to ~<till a ~1·Ilt·ral oH'nil'\\'oftlu- sllhjl'<.i.1It'(,!onlysiudy
SI'('tiollSDIlt'alld Two.fl,!-:t'lllt'r\\ilhChapter 13,Variahility,and Chapter IS. \Ionitoring.
S('('lion Tlm'(' dt'als with til(' physiolc~(' concepts relevant to an umk'rstamling of the
Pl'Oc:t'Sst'Sofabsorptmu.dtvtrthution,and climiuanon. This section forms tilt"basls for an
appreciation of tilt' mat{'ri,tl ill Section Four, whid. is concerned \\ilh the idt·nlifieltion.
c!t'Sl'riptiOIl,and at'('(llllltilll-!of"Iriahilityin patients' rt'SI)(JUst·sto drugs.Coven-dhen-are
~('Ill'ral ;I'pl·(.'h o(variability, (ollm\"(,1by{,(lIlsidl'mtionsof~(,IWlks, age uncl w(·i~ht. dis
t';I<;t', inlt'mdilll-!dml-!s.and lI\(milurinl-:ofdftl.e:concentrauous.
SI'('linll Fi\"('containssch-cn-dtopics.These-<tn' ill!t'I\(II'(1for Ihust·rt'atll'f1iwi\()wtsh10
~ajll a mon- t1f'lailt'(l illsi~llt into curious uspects of clinical pbannacokim-tics.111t" topics
an' distrihulioll kim·lk'S. pllarlllanJlt~(' rt'SI)(J!lSt'. IIwtaholih' kim-tk-s, doS(' and Iillll"dt·
1)('IIIII'I1('II'S, tUnJO\"N l'()IIl'('pIS. ami di:J)"sis, Eud. Inpk' is K{·.lt'rall~· st·lf-<.'(lIltaint,!; tllt'y
ImH' unt 1)("11arnlll~l,1 inany partil'ularst'lllt·m'(·.
CHANGES IN TNIRD EDITION
TIl(' fl.y('ar ~ap hdwt"('11 tllis thinl ("(filion and tllPst,(,(lIld. puhlish,"(1ill 19MJ. is shurtt'r
tlla" tll(· 9 YI'af1i hd \\l,,('Util(' st'(und alltl firo;l 1,litiol\s.nlis shUl1t·nillJ:of tilt' Iilllt· span
Pl!EfACE
IM'tWl'i'lI ,·dilium rd ll'd s tln-l'\l'r-J,:atl...rill~ P,I(~' of p"~n'Ss alld applil'atioll of ehnical
pllarllla(~lkilldics. D,"pill' IlIi, J,:m\\11i. which Ila,\ n'(lllin"(l Ihe inclusion of 1I111ch new
ruatr-rial. ('\('1"\'dfort Il,L' IM"('II matl(' lu (~lIIlaill tln-overallSi"A' ofIh.. book. This. in 11101,
lias meant Ih,;1 SWill' lIlillt'rial llas lIad IIIIx' ('olldellS("(!or dd t'lt'(l. It IIlLs also n's1l11("(1ill
a muc-h j,(n'all'r u,,'of "hhn·"ia!ioll'.(·'I)(...·iall~ for units.
TIlt' 11I1I1l1M'r.topn-, alit! S(" IUI'lll'('ofchapters have h('('11 kept ('Sst'lIliall)"lilt"~11Il(',L~ ill
11.1' \('('(Illd ,-cIiiion, IIIMl"I'r, r-achchapter has b("('11 ('l\lt'nsi\"d )" n-visc..1aml up(lalt"(! 10
I'IlSUf('111;(1IIII'I',-,unpl,·\ n-lnn-10l1IITt'lIlly prescnlx-d dmg),Apartkul,lr ('Ilurt h,L';be-en
IIMd,·III ind lill.' vtr-n..It'III·lIIi~IT\. n,(~~l1i/illC:Ihal Isomers mavImn'dillen'nl kinetk-s and
a(1i\ily.Tll('n' h "I"'l('t>II~id('r,~!ioll ortil(" iJl(:n',l~ill~ Illlmh(·~of IXllyp','ptid,' am! protein
dmj.(s ,·IlII·fJ..,'iIIl! [nun advances ill molecular hioJ,~ and hiol('('hlloll'K\-"' AItIIl)U~h the ki
Iwlk·(lllll",'ph an' lilt' sallw. 1111' phy,illlu'~i~' halllllilll..:: of macmmoll'(11lar compoundsis
'lui'" dislilld from thatofI~pi('al slIIall lllol''('lIlar \\t·it.:lll dm~s.
TIlt'pn-wutationoflilt'1M10k h'LSa["'1IM'''II ruar]«..I1~ illlprowdthroughIh(' Ust·of(:olor.
TIll' mort-nuportuut ("Illalions art-IIOWlIil..:lllighl1'd bvmeans of color.Chapter number
;111.1 ~'('1i'1I1 Ilt';\llillgIIlIWalllM'aral1111'ItIp'If('01(·11p'I,l..::" b~nu! to assistill('mss-rt'fl·n'lIcill~.
.-\ lahll'offn'lllwnll.\ tN·d '~'llIbulshlL..IIt·('1l pb(~"(IIIt'I;lTt.Chapter 110 fadlil;llen"tldillin~
wmlltlk wln-n IH"~'S"IT\'.
The ralll.:1'alit! uumla-rofprobk-m-,al Ihe eud of('adl chapterand AppendixI(totalof
";7III'Wpruh[('Ill';) Ilan' 1"'1'11 ,"h,tallli,illyextemh-dto itssisl in 1('itmilllJ: pruhl('m SU";I1~
illl)haTlna,~,killl'li('s, 'I(lsiIll'lilt, addilillllalproblemsan' takenIrmnhterutun-,rather than
Sillllltt"'i!.Ibt",
Tilt, thtrd ,-c[itiou (1J1llaill\ 102 IWW figures anti 20m'w tables, n:'l1('(1in~, in large P;lrt.
Ill,'atklllt'(', ilIad" ill n"t'('111~";Irsill11liT~'lllwll'(I~(·of111('pharmacoknu-ttcs ufdnl~s.Tln
mun-rtal 011"Small\'UlllllWuf Di~1rihlltiull" thutcompns,-d tilt'ttsl chapter oftilt' second
,..[itlon II'~~ 11t"('1I illlUTJMlTakti intn Cl.aplt'r W. DistrihulioTl,atul:\ppc.·lIdh I-F.
\\'1'(~llIlilllll' 10 adopl a umfonu st'l ofsvmbols 11m!10 II...•lIlilli.t.:r.ulIsIliIN (mwLl,lS
tlu vtaudard 1H,'aSllW ofcouceutranon. \\'e do rt"l.1lj..'fli7'(·. however. tht· illl'n·,t\illJl; trend
towun]tilt' atinplillil of1lI0lMIlllil\ lind haw' pnl\itl'''tla fador for conversion ht'!"Wi'('1I tht·
two lIllilsof nu-acun-uu-nt ill til(' ('ll,'rtiIlPIlI fiWm·captious.\\'t' shallunl~' il(' convtnced of
IIII'virtm-of,,,I,,\y lISill~ lilt"molars~"SlplIl ofmcasun-ment wln-u dm~s an' pn-scnlx-d in
~Ildl Ilnih.
ACKNOWLEDGMENTS
\\'1' \,;sh to thank all tilt· Ulall)" silltipuls lind reatlt·rs w!lu pnl\itll"tl inpul thai Ilt'lp'''lllis
shapt·IhisIhinl("(!ilion.Their1·lllhIlSia.SIIlami{"m"llllr.t~{"IIWIlIhaw'11t'('1llIl,mlillllalst.ltln't·
of salisfill1ion. To 111('1It'\.\· n·ilder. Wt· hnpt· that 11... IItMlk \\ill su('t.'t"("f.1in IlI'lpin~ )UU
<I....-dopkil)('lk-r..a....mill~ Ihal ....ill hI'ofpersonal\,.Iul' ill)'tl1tT pmf('ssionalpml1il"(',
\\'(. hOI\"(' h("('11 ('llorlll(msI~'~nllifil"(l hytill' \\;de allli di\"l·rst·n·mlershipofIIIl' fir.-tIwn
t"f.lilions of tilt" h(ltlk. \\·t· ....,)\lld lik(' 10ht'ii('\"(' Illat lIlt' IItMlk ha..11t'l'1I inslmllll'lItai in
fllrtlll'ring mliollal lllilllav;en)('111 ofdm~t1lt"rdp)',Wt· sinl'l,Tt·ly11Ilpt·tlml Ih.. thinl t'(!ilion
\\ill l'tllltilHl(' 10 do st.1.
,\loltcllt'-dt"r, £1IJ!ol m/ \la!t1.,lm H()\,·land
San Fm'irl~('(J. Calijonl;(/ l1Ullllll'i~. Toz('r
CONTENTS
Definition!>of St:ibols xi
1. WhyC1inicolPormocohnerics? _ _ 1
SIOIONI. "'SORPTION AND DISPOSITION IINIHCS
2. BasicCcnstdercnons 11
3. IntravenousDose 18
4. ExtravascularDose 34
SlUION II. THIU'IUJI( IIGI.IN5
5. Therapeutic Responseand Toxicily 53
6. Constant-RoteRegimens 66
7. Muhiple-DoseRegimens 83
SECTIONIII. PHYSIOLOGIC(ON((PTS ANDIUUTI(S
8. I'v'lovement ThroughMemblOnes 10Q
9. Absorption . 119
10. Distribution 137
11. Elimination 156
12. Integration With Kinetics 184
SECTION IY. INDIYIDUALlZATlON
13. Variability 203
14. Genetics . 220
15. AgeandWeighr 230
16. Disease 248
17. Interacting Drugs 267
18. ConcennctionMonito,ing 290
SECTION Y. SEUCTEDTOPICS
19. Distribution Kinetics . 313
20. Pharmacologic Response 340
21. MetabOliteKinetics 367
22. Doseand TimeDependencies .. 394
23. TUfnovel Concep's .., , 424
24. Dialysis ,443
SEUCTED lEADING 463
APPIHDIX I. ADDITIONAL CONUPTS AND DUIYATIONS
A. Assessment01AUe 469
B. Esnmct.on01EliminalionHall·life flamUrine Dote .473
•
CCNTENf5
C. EstimaTion01Absorplion KineticsF,om PlmmoConcentration DolO " ..,." 478
D. f'.h:Jon ResidenceTime 485
E. Amount ofDrug in Bodyon Accumulation 10 Plateau 490
F. Oislribulion ofDrugs Extensively Bound to PlasmaProteins "' ,4Q4
G B!cxxi 1o Plmmo CooceollOtjon Rolin 502
H Esllmorion01C,eohnineClearance Under Nonsleody-StoteConditions .....504
"rINDII II. uswns [0 PlOIUMS SOl
IlIIlI.XL -"110
586
DEFINITIONS OF SYMBOlS *
Amoullt ofdnl~ in hody. 1lI~or A... Amount ofdnl~ illIxxl)'at steady
umolo. state.' duringconstant-rate mtrave
1I01lSinfusion,mgor IJIllO]t',
Atl Alliount oft1nl~atubsorpnou
sit(· n'maillin~tu he.' absorbed, A...... A\'erdge amount ofdnlg in Ixxl)"
1ll~or "UIIO]t'. during adosing Intervalat stead}'
state. mgor umole.
CUlIlulathl' amount ofdnl~I'X
A..,......: Mali:imum and minimum
e.'rd("(,1U1l('hatl~('t1 in th(' urine, A.........
Ill~Ofj.tlllole. amounts ofdnlg in Ixx!yduring a
dosing Interval at sll'lld)"state on
Ad(",) Amount of lllt'ta!xliite ellmtnan-d. administeringa fiu'tldUM" at a
1lI~ or umole. fixl-c.1 dosingInterval, m~or
CUlIllilati\'{' amount ofdOl!,!:ex IJIIlO!t·,
A....
{·rt'h,,(! lln{'h;U1~(,,(! in rlu- urme Amount ofdrugin bodyat lillie t
dllrin~a dusill~intervalat sh';ldy \\ithina dosing Interval at stt·ady
stun-, 111~Of umok-. state Oil ;u!millish'ringa fin-d
dust, at a fi\I-c.1t1osin~ Interval,
Cumulative amount ofdm~ex
IllgOf umole.
(:rl"lt-c.I IIIle.·h;U1~t'tl in tilt' urille to
lilllt' infinity aftN a ~ill~!e duse, AVC Aft"a underthe plasmadrugcon
mgor j.tmolt,. centration-nmecurve.Total un-a
fmm tinll' ()to infinityisimplied
A(",) Amount ofmd"hulilt' in Ixx!y. unlessthe local ('(mt('lt indicates
1Il~Of j.tll1ule.'. • a specific time Interval.e.g,. dos
TI\(' minimum umouut ofdm~in ing Interval, mg-hr/l,Of1J~I.hr.
Ixltly required to obtain" pn-de AVC" Totalarea underthe blood dnlg
tennim-dh-vcl ofn'spoII~', m~or concentrution timt· curve, mg-hr!
"UIlO!t'. L orp~l.hr.
Ay ......: ~lll\ill111m ami nununum AUC(m)An'illlml('r tlw plasmarm-tabo
A,\',.."" amountsofdm~in I)(ltlyafh'r the lite concentratmn time curve.
Xtil duSt,offi.'H't!sin',wd¢\"1'1I mg-hr/L orIJl\I·hr.
at a Iixed dosill~ interval, 1l1~or AVC.. An'a under the plasma drug
('()II
umoh-.
centranontime curve within a
"\\'., Amount ofdnl~in I)(xlyat tilllt' t dosing intervalat steady state,
aftN till·Xtli "O\t', 1Il~Ofumole. mg-hr/l.or IJM-III'.
,\V.\lC Total an-a under the first mo
Amount oft1m~ (t'maining to he
mont-time curve.mg-h.-2/L or
t'xI'n'It-c.!ill umn-arkra smglc
1J~1-11.-2.
dose-, mg or umole.
c
Concentrationofdnlg ill plasma.
·C."..I""iI'"n'10"'''. mwLorj.t~1.
..
..
DffN1X)NSOFs,r.w!O.S
C(O) Initial plasmaeoncentratkm, lISU- C_ lIi~ht',1 {Im~(''Ull('t'ulr.l!illll lll..
all)'obtaintodb)'('droiplKdHflll to ~'nl'tl in plasma follcJ\\ill!{ad-
time 7...-ro.mw'l.orJ.lM. milli,traliollofan t'xtm''lL'ol'1llar
C1:C2 Coefficielltswith unitsof<:(m('('I1- tic.....•• mWl.llrJI\1.
trarjon, m~'l.nrpM. elm).. COlll't'nlrdlioll ofa IIIt·lal.llih·al
C. Ceucentration oft1nl~in fluitL..011 \tt·;"ly ,t.aft"durin£:a ('(m..tam-
the;j,~lTptiOIi ,itt·,IIlWi.or",\1. rate illtrd'l'IKlU" inf"sinllof dnl~
C" C.tllK't·ntrolltnll ofdnl~in arterial IIIWI."' J.I\t
blood, IIlgfLor J.I\1. C_.. \lilliullIlIl ('1ltK't'ntr.tlinn n"Cluin'tl
C, ('.ou('\'ulmIKlIl ofdnl~in hlood. 10ohtain a pn'tIt.It'nuint"l! tnten-
mWLor J.I\1. "ity of n~llClIIs(·. mWi.or J.I\I.
CINI CotK"t"lllmfinlln(bounddOlI-:: ill C,\_ .: \I.uillllllll anduuniunuu ulII<.'('n-
plasma, IllWI..or ~~1. C\'~" tnutons ofdrug in plasma afll'r
C'J Dnlg l'lIIK"t'nlratinnin clial)~II(' Iht,XIIIdoS{'nn ;tdrnillhll'rin~a
Ic'a\in~diOllp N.mWl.orJ.i~1. fi.\t'tldoS{' al cquul dosill~inh'r·
vak IIIWL orJ.i\I.
(;1 CtJlK't'nlrllfiunnfinhibitorofII1t'-
c.;
tabohsm.1Il1i!.or ~\1. CUlll't·ulr.lliunoft1m~ ill Ill'rill..
CI. Tot.al clearance ofJmgfmm lll'llll'a\if)·, IIIWLnrJ.i\I.
plasma, lAir. C. CmK't'lIlmtiull ofdm~ ill plil-\IU;.
CI.." Toealdt"ar.lIK't'ofJmgfn)lll al ,11';11.1)"stOlf(' duringa n mslanl-
hlt:n.1. lAir. ran-inlr.l\1:"IlCItISinfusion, mWJ.
ur J.i\1.
Cl..",) ~'5isclt-anuK."'(" ba.~'tlOildmg
l't"K'(·ntr.ttioo in hluu{!. LAir. C.._ ,\\l'r~{'tlnlg conceutrabcu in
CL"II Hepaticd(~.u-dIKTofdnag from pld.\lIl4/,cluring adosill~ i'JlN\~J al
hlnnc.L lAir. stt-....I)·slalt·011 d(llIIinisll'rill~"
fi\t"d diN' att'{!ttal dosing tnn-r-
CI.~ Ht"taI d('llrdlK"t"ofN\·dlillillt-.
vals, mWJ-,.or I-I\t.
Illl/min eN" lAir.
ct.; Dial)'5isdt'drdlK't' ba.'\t'll011 dmg CC.....__.: ~la'{illlllln and nuninuun t'(lIl(,'I1-
Irdfiemsofdmg ill pl.tSIIl;& af
couceutrateon in pla.SIlla..lAir.
Slt';lcl)" slaft' em adminis!t'ring;&
C/, Clearance a\sudaftoe,lwith Forma-
fi'{{oe,ldust' .IIequalclusing inte-r-
lion ofa mt1a!J,olitto fmm a dmg.
vals, m!ifLor J.i\1.
lzhr.
ct.; Hepatic dt'amnn' nf dnlg from C, ,\\'{'m~t-courx-utrutjon ofdnl~ill
111li,Lsuutshh-plasma, IIlWLor
plasma. lAir.
JAM.
CL"" lntriuslc ck-aranee ofdm~ illor-
~an oft'liminalioll. lAIr. Cl'" J)nl~("IJ11c't'lIlmfifn)IIl1hollllclill
lolal hoc.I)·wate-r. mWI--orpM.
CUm) Totald(';\mn("l.'ofa rm-tabolitc.
lAir. C - ~1a.,iIllUIll and minimum limits
.",....
CI·,.u Peritoneal dialysisdC'ardlK"t' C"....... for pla.'lIIa dnl~("Ilnn·nlrdfMms.
1llWI--orJ.I~I.
basedon dOlJl:("II1K't'llfrdtlon in
plasma. lAir. C" Unbounddm~(·ollll.'llfr.ttion ill
CI." Renalclt".uaIK"t'oftlmg. tAn. plasma, mWJ..or)1~1.
CI..fl Ck".u-d1H.,·ofunbound drug. CII, Unbound plasma(.'t)lK't'lllmlioll
lAIr. of illilihilllf, mWJ.or 1-1\1.
C(m) CAIIK."t'nfrdholl of ffi(1ahofilt' ill C,_ C.tIlK"I-utr.lIMlIlofdna,::ill\"('lltMIS
pLaSIila. '"WI.or 1-1\1. hlcMII1lIIWl. or J.i'l.
DEfWlONSOf SV.YaQlS .~
IJ,. Luadill~dose. m~or ~.IInClI('. t". Ralio ofunboundconcentranon
in pla.\lUiIand lotal dru~(,(JlK,'n-
\laintl'llalln' dn"", ofa f!Wtl.tlOSl'
IJ"
tranou in blood.ununits.
n-WlIll'll. 1Il~or~ullolt"
Uv__ \tuillllllll mainft-ll<.IIK,(·du!>(' 10 ft·, Ralio of unboundand total sih'S
r-u..un- th.d tiM.'plasma dm~con- a..'iLil.r.bk for bintlill~nn a pla.\IlU
('OI'ntrat~>II "'III;UII~ \..ill.in C..,.,,- pron-iu, 110 units.
and C.lo.......Iimilstillrin~a (k)O;ill~ J"ff Ratio ofunhound and a\'('r.t~(' tl..
Interval at steatl~' ..tate. 1Il~or tal dm~rono-ntrations in intra-
~Illlllt"
t,'lIl1lar "uids,nounits.
F. E,tr:.K1illllratio. 1111units. fliT Ratio ofIIllhoulltland total dm~
IX :',II {;onn'ulratioll ~i\ill~one-halftiM.' conccntranons in tissues (oubidt'
ma"iIl1ll1llI'lT('1. IIlWl." I' ~\I, plasma). 110 units.
E" IIt'palkol'\lmdiull rutio,TlUunits. y Shapl' factor inconcentration-
f:,..... \I,l\illllllll('lTl'1,uuttsof re- rt'Srx)IJ~' n-lanonship. 110 units.
SIXlIIM' uu-asureuu-ut. GfJl Glllllwmlar filtration rate. 11111
P Hilla\~libhilityfirdm~. uo units. mill or l;1l1'.
h..1 Ratio nrIXIIIIIII til Inial dm~con- k Eliminatilln rate constant, hr- I.
l'Ol'lItmtilllls ill pl.eeua. nil units.
/;• AS\lx1aliollconstant for tilt' biml·
t" Dial"''iiscl..aram'e-as a rrd(1ionor in~ofdrug10 protein. 111J1olt',
tUlal'cleamno-dllrill~a (Iial~"is
ka Ahsorption rate constant. hr- I.
In'alllMOlIl, no units.
fi· Fraction oft1nl~"'~....te-uuc-ally k" Ehnunatjon r.lIt' constantwhilt' a
...."".liLahlt'11Iat i",l'uTt'!l,lun- P"'tiMltis undergoingtlialrsi'
t·han!:t'llin urine. lin uuits. In-aIIlM.'nt.1Ir- I,
FEV, Forced(·xpirdt()~·\UllInK'in I k. Urillal)'escn-non rail."constant.
second. I~ 11f-I,
"'" Frecnouortlnl~t'likrill~tht' k Hatt' constant ilS-\lldatl'llwith l1.t'
J
live-rthai Ml'ilp'-sl'limirlalioll 011 formation ofa metabolite, 111'-1.
singlt' I'la.Ssa~l' tllnlll~h thai or- ,
/; Inhihitiont"fluilibrimn constant,
~all, 110units. mWL
or ~~1.
Jm F"rad:iull lOrIlnJ!!: sph"Illit-;JI~'
k(m) Ralt' constant for the d ilUina!ioll
;l\'ailahlt' thai h t'(lI\\'('r11'!to a
ora lIll'taholitl',hr- I.
IIl1'l:llx,lilt'.110 units.
fill Fraction or..dmini..lt'r,,1do!>(' or Am MkhiU'IiS·\h·uh'ucoustaut, mWI.
dnl~that l'nh'f'!i till' J.:t'llt'mlcir- or ~\I,
l111..-liou usa nu-tabolin-,no units. I'm' \lichal.'lis·\leulenconstant.t'X-
F• Fraction offiln-n-d and !>('(:rt'It't! pressed in terms orlotal plasma
drugreabsorbed ill tilt" renal tu- concentranon. mgILor p\l.
bulc, no units.
Kp EqUilibrium distribulion rdtioor
ft· Ratio (Ifunl.Jl.lIltland toraldm~ dmg ht1\l.'t...n tissueand hlc...1or
('OI.IK,'ntr,dion~ in plasma. no plasma. no umts.
umrs.
k, Fr.K1tonal rateat which dm2
I"' Ratio orun!'numlilut! hltal dmR ko""'S tis~ut', hr- I.
('OIK'('lltmtioll~in pla...ma Ulld("f'
k. Frat.1tomlltUITMI\"t'r r.tle,hI'- ',
t'Uullililll\sora1tt'n,1 bintlinR-no
I
units. )...; )-t F.\plnt'lltialcoefficit'nls,ltr- .