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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 .. I lth~, subj ..d . (R..,lr,,"'·n rm m 8i .·~ ..I, U., n ,,"n....'. T .. W,'h" T, W.. n..-Iwr, J .... 801("' no, R., S ilT. ),1.. ..,,,1 11:....,il7., II . I'han ll... ulj",,'t~ or ~;u" Ih;omi...· in I"",,,. ns ..n; 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-8 8- 12 12- 2.1
"""" o ... "" 120 180
BO
340 178 ' 50
CCN:f:NTU ,~ '"
'NO.N
="",,,,0
"VCWlT~
""" N " "
Im ....Tf lll,'A!. ("'\J"/ll
"'''' 133 50 63 10 18 2
" (tfIl D
C UYU./l 11VI
N"" ....J!NA!.
~""-'" H C91flO
...
'
' 00 226 14 0
'6 0 00 56
0 66 0 80 0 43
34
32
"
...
160 250 30 6 34 0 372 391
Plasma Data Alone A p lot o( p!;Lsma concentranon versus lime illdi("lill' s that IIII' \·alll('s an- dmppin~ p n ~n's sin,l)", hilt o nly a(h'r tln- da ta an' ploltt'( l SlCleloon dolo IoIIowing exfrovo5CUIo, administration.
Fu r sys h ·mie.llly ad i ll~ dmhrs. abso rp tion is a pn-requisin- for t1l(' mr~ 'lIt i c adhity wln-n Iher an' a
n it"
imp,,(:t o f rate and extent o f absorptton o u lJott. plasma ouux-ntration andamount u f dm~ ill tilt' hody; tl.t' d Tt'\.1 of a!tt'mthllls ill ahsmpliull alltl d isposition 011 hull y k-vel-ttunn -lationshlps; ami Ihe methods used to assess plmrn \;t(:okindil' paramet e rs fmlll p lasma undurinary (Llta foll()\\in~ e xt rava scula r udnuulstrat ion. The term IJ;{I(I lA'lilaIJllity is l'CJlIllllollly appliloO to IX)jh rate ,lilt! exh-ut u f t!0l ~ inp ut int o tilt' sys te rmc em ulation. 11mm glJollt thi s book the term will ht· Iilllih'(l to tilt' extent of drug input and can 1M.' conslden-d as the Fraction, ur pcrwnt . of tht, aduuntsn-nd dust-, abso rh{'(1 int act .
KINITICS Of ABSORPTION 1111' oral ahso rp tion of dm~s ufit 'li approxiruutr-s first-o nlt 'r kiru-ucs . {'spt"li;llly when Wn 'lI in solution. Th e sam e holds true for the absorption of dmw; from llIany other extravascular sill'S i nd \l(li ll~ subcuta neous tiss ue and 1Il1lS(·II'. Unde r these ci rcumstances. uhsorptiou is d l' rdllR{' fmm 15 min til 1 lrr. OI"l"il-si'. tilt')" an ·lflllgt'r .
OWTE ~ 4
Souu-tinu-s, 11 dmg; is ahso rll("(l al t"s11ca,,_ '" ,,,.l.t~ . lUlIl .. \c... .-rilti/: {If II""I",·ak l". Il, ·nlr..tio mII rnlo1I. .. .5,.5 j.I~ l l . ( ~ I , ..lifin l frum ,I... tLI... of Re... L,,"!. ~I " 1\;."·I,,,all. S., I I..m •. 1', .-\.. ;.... 1s l...Il"lT. S I)., ...I""'1>1io" l i,....Il... tI'tI..1t1, p"' n n i"
it ll l
,i ,h., ("I~~J I '....' ItT )
EXTiAVASCl.J.AR OOSE
"
TIl(' h iua\Oiilahilil)', F, is proportional to the-t otal urea lImlt'r the plasma couceut ratiou-time curve (r\ Ce ) irn'sl)("(1in' of its shape. T lns must la- so . Heeall From C hap . 3 th at :
T0101 a mount eliminaled .. Clearance ' AUC hul tl.t' lul,ll a mollnl t·!illlinatt'ti is
2
tilt' r..pl, on lilli""" I, al....''1" ioll' II,Loo.·1< li'''' l r.." , h",i l' ..h", i"" lio." "" 1"" 1, I.·di 'll( li",,,,r 1'10" o( II... I''f' 11m..' ~pl" ) an ' itl.'nli, ,.1 n M "..H ·C. Ilr tI.., Ii'''';or pit" . or tI,,· n" I.. d..t,, ;oll' 1lI.. , "'-1"llIl .."t'au't' II inl' V .,] or th.. ....1(' of ah" ''1" '''lIl, ;0""""" ,,1....,..+....1. '''I'''''' II,,· inh V ,,] o( I...· ra,....f r h",inatio", """..",t ..Ii"'i, I•..I.
,I,w,
3.
fKlRAVASCUAR 005£
CHAPTER 4
ah sorptio n half.llfe. All other fat1nr.; (hio' l\1Iiltlo n .,f 1I"''1>1,., lIi,,.· " ,. . .1 r~>i, 1 .. ~ ..·n tI... ,,,h it.., "" ' 1'1 ' di. ...>1""11 ill
6
c
T" ., lal.l 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 . ""!,h",, Li'", tin 1... " 11 ",, , ah"''l'Ii'' '' r.lt,!' rnhl.· wit l,
l li,..·. I. ,tt u lIl l::r..I'IoI.
lo",,· ) (, .. "'
110." ".ItI lill.. ,l IUN', h"tt"", 1(,,,,,11 1.
1000
,.1,·
500 _ Absorption
~
200
S- 100 ~ a:
/ / Elimination
50
r
20 10
0
4
12
8 Hours
. '11:. 4-8.
B,'
,
,
,
,,
,
, ,.
,
,
,
,
Me mu ry aid to ;u... u du. np:l'l in pt'a k
Iim.. . nd prak a moun l in the body. ftl'rnlravalMIla r ad m lni l tnatlon o f ;0 IrinKJe ,) n . b. m rpt lo n or di~i1iun " . It..red. n... tiYr pt'u 11m.. anU Ih
CHAPTER.4
42
2.0 Fl~ . ~9 .
,e- .,
\ 51"'" ""
, ~ ...... i. 1/;i"'" ;,,' r"""'''-~ II...I~·
"'K IIIr.J I~ (0- .
"-",,m'h' ,
" ..1", ,.1
·0) h. tI..· '' 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
I"'!ravenous
3010
Scbcccrecos
1372
'--...::I _
~
"'"""'"
«c
~S!~"TO-'
0
f~
( U
•
~"""""""I'QhfI"'"~nglo _ ., _ ...... I,." I>oc<j ~
wa> "' ''''
COt<EN1lA10'1 .....",
4 17 40 ,5 >
"""""
8 . .,... 5ctooooalo . M
_
67 ....... col
_~
'--
of this d m~? fl. Bt·sllyah d ul. ( Bt'shya h. S.A., Anyanku . V.• S ilhthya lliUllhiln. n., Sharp , P.• and Joh n. ston . D .( ;.: 111l" d Tt'(:t o f SlIht'ula lU'()IJS injec t ion sitt' o n ah smp tio ll of hu man ~rn\\1 h
hormone: Abdomen \,(' fSUS t hi~lJ . Clin. Endocnnol.• J .5:40H- H 2, H~Jl ) examined the l' lTt"(:1 of s.e. illjl"- but. unfortunatr-lv. onl>' Iimilt "f.1 lnfor. mali! III is 01'11'11 uh la inah lt, !lt' n ' a"ulil Ih.., nature of the dmJ.:- rt·(-'l 'ptor tntemcncn. /II l:itm cxp -rtnu-n ts. wh id l indmk' studn-s o f the act ion of dmgs Oil ('Il7.pll(·S, receptors. mien.. nrgallisllls. ami isolat r-d tiseues ami organs, st' l"\"(' this purpose Ix-st . lI oWt'\"(" , in iM,I.ding tht' variah ]"s , lIlany of lilt" comple-x Inte-rn-lationships that ('xisl in 1:1..,., are t1t'st n ~l 'tl. Animal Silltli('s hritlJ.:(' much of tjn- J.:ap h..'I\\'("'t'1I in t:it m t'\pt'rillwlltation and hu man tnves tiJ.:alioll. Studies ill animals introduce bot h lilt' variahh- ti me, with all that it connotes. and
Thercpecnc WIndow
Ab>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', 111is narTO\\1lI'SS ariM'S hI" l'ilUSt' Iht' n 'spoll."t· t-urves IM'rlap wellbe low Illaxima l effiCill')'. so that it is d iflk 'u lt to find pla.s lllill·om'(·"l r:ltiol s Ihat produo- t·ffil'ill'">, without SOllie tI~n"t" of limitill,glo"idly, It is In ht· stn 'sst'l ! tlcu si,,~n i fiednl intt' rilltlisitl uill \"ariability Illil" oc cur in hot h rlul.ffil'ill'y a lltl tm id ty n.·SptlllS(· curves . It'ail" shot1'
,/
If
li"..s).uu." lr..i,,"-
I
I
('OIl (-. ' Il ! n. ! i o ll · r(" p\\'s tin' relationship lx-two-n the steady-state plasma concentration and the rate of ad nnmstra tiou of plu-nytom. ('xpn'ssed as the diUl)' dose pt' f ki l ~ram o f bod y we ight. "111Cn' an ' larg{' inle rlndi' i d ual dl....-iations in till' plasma concentration at all)' dosing mil'; in till ' patiellt cohort stud ied . tilt' plasma concent ration ran~('i l Imm JI('ar l)' () to .50 mWl. when the dosiJl ~ r ate is 6 lllWddy/k!!: o f hot ly wd!!:t.l. Had 110 correction bee n made for body weight. til!' dt"\;a liolls wo uld han' h('('11 ("\'('11 ~n'ah'r . III contrast, plasma concentration ccrn-lan- s n -asonablv well '\ilh effect . Thus. seiz ures art" usually effectively controlled at concent nations hdw('('n 10 an ti 20 m!ifl.; sidt' t'lTt'li s O("(1 1r with inl're asing frt'tlue nl')' and severity as tilt' pt Lsma coucentrunon exce-eds 20 mWl.. as sho....-n ill FiF;. 5--6. The fin l si?:JI o f toxici ty is usually Ilysta~m ll.s . whkl. apr~.'ars above a concent r ation of approximately 20 mWl.; gait ataxia usually ap pt'an wi t h a cencentratum app roach i ll~ 30 mw'l.. am i pRllonged drowst m-ss am llt"i hargy lIIay bt' seen at con centrano ns in exce ss of 40 IllWL For phe-nvt oln , plasma concentration is a be rter correlate than dose duri ng d m mk ad ministration b{'l'au S(' ph arm al'tlkilll'tit.'S is til(' majo r source of va riubility ht,ty,'('t'1I dose am i rt'Splllls('. Fo r other d m gs, s1I(·1I as umpictlhn. pbarmacoknu-ric V'd.riahilit)' within tht' patit'llt population is n' lati\l'ly small, ami variahility in the concentranon-response cu rve is la~l" In such cases. plasma concentration is no be tter a correlate ....tth rt's rxlllSC than dose am i int!t'{'(l may 1)(' "UfS(' if. for exa mple. met abolite s con tribute to act ivity and toxicity (S('t' be-low, Addi tional C.ollsidl' r.tlio ns).
ADDITIONAl CONSIDERATIONS D('spilt, the appeal. meas urement of plasma concent ration is rt'latin·ly UIl ( 'O mJllO I\ in d inleal practice (St'( , Coucentruttou vtonnortng. C hap. 18). Tilt' major rcusou is the ....;dt· margin of Sh,,1 1o·....Is, ;11,,1 tnu(ity. An"', :-..."n.... 1l :6H----64,). 196-1 . Cop:o'rill:ht 196-1, Am..ric-lIll M ...lIt..I A-."i",li.." . )
.2
CH....PTU 5
Active Metabolites VillI's>; ..eth l' Illt'talxllih' s an ' ,,1 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;llIa.< ".. d1a IlI(.·
111
.l.oi l~·
,......" ..1 .. i llo
100
~'n l ...
,nI
The Pioleou Value :\ t an y t imt· dll ri n~ an in fu sion. tilt" run- of d"lIl~t" in tlu- amount (If dru g in till' hot ly (tI.Vtltl is tht" t1i1Tt"n·m'i·IM.·h\"t't '!1 tilt" rates of t l m~ tnfuston am ] elnulnanon.
dA
"' or
t·\prt·....ill ~
tilt' equ.uton
k· A Cc euc nt role o f inhJsiOll
Rote 01 el iminotioo
ill terms uf the concent r atton
of d m ~ ill plasma.
Used lor i v. infll5ion Soma ~ a le pcrtIble. o/he<s O' llt implanloblllt
30.60. a QO mg/dov
001
odm,n'!>Iefed do,ty
f't>enyIproponolom'ne
25 rng rrreedoe ,eIeo~ and 3 4 rng/ht for 16 hr
Coburn ehannelblocker l\Iond's,nltlg'Ol,ng S)'S1em is designed 10 proede a eonSlont 'Ole 01 -eecse lor 2411, Appel'1e suppressont System o,ms 10 prov;de a (OI'\$lQn ta nd effecb...e plasma ccecewcrce 01 pher¥prop:trOOm'ne
16_ Tmn$do><mol
00501 0 .1 rng/ doy
for
Treo lmen t 01 menopausal syrnplOm$ and pl'l!'\I'llI'lt>Oll
01 O5IeOpOI"O$IS
AppIoedlO Inlrd:, 01 body. inck.d"''oQ bullOck! a nd abdomen. TWice ~ty
7, 14. and 2 1 rng/doy (40 ltg/ em1/ hrl ehonged doi/v
o I 100 6 mg/hf oYttr 1211,
b"0'''''''''''''' .
M Pr~ a 'eoloOllObty conSlOnt plosma concenllQ1lQtl 01 nicotine Polch pIoced on front 01 bod above 'NOIS! 01 on uppe< outef pert 01 o'm p.ophy4o.'s ogoinS! ollOCk 01 ong,na pectoris Syslem a"T~ 10pl'ovide a (OI'\$lQnl plasma concenfTCll>Oll 01 nillC9!ycerin Recommended oppliCOl>Oll S11e
o 5 rng CNef 3 days
's Ioleral cbes M;lW
U~
lor prevention 01 mellOn
"'.......ho,f\es.s Applied 10
area
behindeo' o, leos/4 hr beiee theonl~1( elfect
n deseed
.
CHAPTH 6
CONSIANT -iATE i EGlrW: NS
t'IJt. 6-1.
1>Ln",,,
n l l'
lUll"
't
•
1500
lil.., "r11,!lI ....h n n-c i...'. (UU Mt·j!,.. " n il "/ rnin
/ 1.-1 ruWlIlin ) ~' ('t'fl>tallt'TlIll ' in f,, "'''' rur /:Ill ,n ino At th. ' " utl u( II... infnsiun. IIo" I'I;o." n.. t· r A ('t" K't'nl · linn tin, .. r"l"'lI)' 1, ........1 1' ....' wilh .. S.2-min half·llf... nN ' li".. i. til.. f"ndi" " C . 1320 ' (1 _ .. _ Q lnt) l l" ri"~ tI.., i " (,,.itll ' .."tI C • 132l1 ' .. - 0 .1. "',. ..
lI...n''' (''-' ' TIlt- , ,.Ju., ,I
1000
500
11,1.11. mill - I ('Orn "l"",t!, In ;a h"tf· lift, uf 5.2 mill . (At4Jt 1 ("»11 K...•
t',.c......". .
10'1'. KW.•
Ka'f'l·r.
\ lIn
A
KI" rl. C .•
til., Williw, I'.A.•
o
"".1 W....tl...rJ,.·, R,C.: n... rJ...n nll ' l'o ~ i '1l'lk. of dcubl.. -charn ' · I' A (d ",,~):
en,,«
or I,,>lu> injo"C:-
o
40
80
120
160
Minutes
lin" , in{" ..o.... a,.. I . I",I"I" ...41i"" I.,.· ....-i¢ ,t in p;dM'1,b "'itt. rn~' Il"olnlial infa,,";" ". elin. l"hann;K", 1 n ......
5O:2fi7- 2"jj. l!:l!:l l. )
100
t
90
-, From infusion
75 ~ ~ ~
~
!,. 8~' 3.3 It.df·li,'t"5. II..• a,,,,,,,,,1 In 11... I u.~ ...." ,,·;;." ..1 will. II..• i" f"';'111I n·;o' is mra n n·.~idl'lln· t jllu' ( .\1 HT) , T o appn' 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 Ihat a ll lJlaini n ~ in ti lt' bt l ~( I 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 atio mhi ps; Ilw)" show ho-v til(" a\·e rJ.~l> amou nt ill till' htl
Half-lives 8etwftn 30 Min and 8 Hr Fo r sud l d m gli. tilt' llliljor t'1 ll\Sitll'riltiolls an ' tln-rape -utk- index am ! t'l)lln' nil'nt1' of dosin.g. A ( Im~ \\1111 a hi.gh tlwrapl·ul i(." intll'x llt'l,(! only II{' administe-red (IIlt't.' 1...·1·1)· J to 3 halfli\'l's. or 1' \'1'11 It'sS frt'q llt'ntly. A t1mg \\i tll a low t1w rapt.'u tic index IIII1St I'M' ~\"t' ll appr ocIllat t'!~· l'H'l")' hal f.lift', o r uron- In-quently. or be WH'n h~' Iufuston. Lidocaine, fur examph-,
500
~
.~
t·i~. 7...1 . Sl", ld, (If Ih., am'M,,,t nf 111r.lo(;'·' dill" in II... I• • ~' Ii " ... ; . 1" ", 1,&1;'", " f II" , t \ '. ...lmini, lr..linll ur SC MI Ill1/: illill."l1... ;tiM! 2.'50
"" ,l.
A
"e
~C;
E ;;; -
~
~
0 ~ 0
250
B
-'"
. 0 0
0
"'If ,'\...~. " I,r 11,,·n·..!t,·,. ('(.,,~' A. \\1"'" ,I"· ;u"1 " loIi nh ·I.... M.... I],...-s .In· II..· '"Ill" ' , ll. il taL.,. "Pf' nn.i ""'tl·I~· .10 I,r (3 I" 4
j" il iIt!fy high lhe2
c.oL Occcececr gIven once
weeUy, or leu I,eq,*,~ , mc.Jyneed
IMIO!
ceee
Sulfamerhoxozole ChloroqUIne Iwppre»ion malario)
aI
fQ be much glea!el !han ma'""
eocec e dose 2
>241'1f
......
~","""
............ _
0.5- 1 ......
~.
C1a....d,rwl' l1equile$cOleful conlfal. once fQxl('Iy ;$ peodcced drugcooceeeosce cod IQxic'lydeclu-.e ~
..-.. ............. _"'0 io<Jd,r,g doM doooogo ..
0'9 'IO>
""'" ~11rle
prop:mohn,roe
Pbeoobo.buc! oc;.- t>,- .. .. -I
.:~
" ,.Ow.
Af H'() Of ..-mfa,/.'
05 025 0901.6 ' ··O..,l1 - ..
'~
~"'~_-I·O",
"''o'f 9.AGf: "'I SIEADY ST"'TE&
""""'"" '"""
"....,.,,,
SlAtE'
ST ATE~
360
500
40
250 10
556
526
22
540
'"""
CHAPTER 7
92
TIlt' s anu- dosagl' n -gill1('l1 fur pl lt'llol l6 allI l :'S2fi n,~
;u't"
8
16 24 Hours
32
40
60Il
p1..·,,,.t>;cr .
hit;d i ll II..• IM"I;o-' with lim..; .i m "t.t~ I" ,of :)II lUI( ~ n I» , ,,,,.. .,'!l hr. JWoooOl... II... l~df·bf.·. 4 '~'" P tn·,",,·J:.· 1,,rt. ,Lt.,IIt..1hn.·)11... mi" i",,,,,, n KK.·n l r-..Ii,..,
lilwliholJd of ("Il1lip lia lJl ,('
(M'n 'n t)' illlt i llillu rt·
of di M':L""' , oceu panon ( If path-ut. !It 'NlIlill ily
of p;i1ient ) am i t!lOSt' rt' lal in~ to tilt" pll
rt'Spt't.·lin·I~·, 111{, sltMl)t'ss
(If dn l~ absorpttou alTt't.i s lilt' dt·,gn 't· uf lInl1l1atinn around. hilt va hlt' of. til(' avt' mV;t' {'llll(...-ntration. T Ilt' t'xt" ptiun is \\'11t'1i ah"u rpt inl\ Ix'('u l!wS so ~ 1(Jw rhat then- is illslllTk it'nt ttnu- for comph-te abso rption. (' .V; .• wln-n !imi!t"ll hy tilt' transit tim t· within tht' ~;l,tru i nh's t i l lill trotti , 111(' dlt' mpt-'util' imll;l ~llid i ll~ prt uciph-
is lu maintain tlu' sa me rate of admt ulstrattou am i tllt'n ·fon · tilt' same chosen a\'(' rd~t' steil UI.1'"xl. n( .101'Wl..... n,.;nx-n ,Io~i!:lI. Il''!:ill w n ..\ b n li< I I>I. d :. lmd 10 .Io-ri~II ..I I" m.
o
12
24
36
o
48
24
12
SUIll
36
l)f Iht'
48
Hours
Hours
t' It. 7-9, I>w"'" l""In·"lr..hn", of" ,Inl~ 1:1"''' illlr.." ·"..,,.ly (I.·til ar.. 1m ally (ri!tl,l) "" .. 1i",,1,...... " I" .')41 m~ ..,..I Ii" ..1," "'i,,!/: inl.·.... -..I nf fi hr . nIl' ""'1"·lil",· i. 12 hr. :'\,,1: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 j' of adill:t7.nlalll of III(' {'tllilmlll't!-n·!(·a....• IJrll(Illl1 ('()lIlpa n1 1In till' illllllt·diah'·n,ll';l'i(· pnl(lll{1? e. {\ n ' IIIl' phart lla('()].';m1ks of udiuaz olam afh-r udmiut stranon flf til(' Iuunedlate-reIt'iL\p alll! tlu- (ulltmllt1 !-n,lt'il'i(' products such that tilt' terminal half-lirt' m il II(' tll'lt 'rtnillt"(l \~i l i l i ll the- n ',,(x"(1i\'t' t1u"ill~ Inte rvals at plateau ? f. \\1...1 are tln- d( '~I't "('s o f accumulation a\StM :iaft"(l wtth the illllll("(!i;lt('-fl,It"l..'it' anti lilt' coutrolh-d-n-lease n'WlIlen~ ~h l' n tlml IIJ(' AVC(O 10 N IIr ) and AVG(O to 12 1.1') f"llu\~ill ~ tl.t' ~ i ll~II' 40-m~ imm(1Ii;If('-n·ll·a..'it' product and Ihe fiO-m R conrrolledn,II'a\(' pnM!lll1S an - II,-l.') and U,-l.J mg-hr/ l.. n'Slx"(1i\'d>'? Ba.'it., >'tIur calculations 011 ..\ l"G (~IIl~ i dt'm tinn~ ,
I
Se c t i o n III
PHYSIOLOGIC CO NC EPTS AND KINETICS
MOVEMENT THROUGH MEMBRANES
OBJlCTlV£S The Ieode!' will be able to: 1. Define PJuive and focililoted diffusion. octoe tronsport. 000 permeability_ 2 . Di!>l;ngui!J, between perfusoon role-limited and permeability rote-limited passage 01 drugs through rrembecres.
3. Descnbe the role of pH in the movement of drug *lfough membrOr"l8$. the cceseqceoces cl the levefsible IlOture 01 ~l 01 drug$ through men't
4 Describe bra~,
So far ill tl.t· honk. emphests has lx-en placed 01\ k jud i IlIt 'mlmlllt · I II anot her d ifficult . A des \lllllll W S of tilt' ll:J1 l1 pa rt lllt' lIts , to and From wlJidl til(' dm~ is transported. a n' small. Initiall)', when all tln- dnl ~ is placed Oil Ollt' sid t, of tilt' lIlt'lllbr.lllt' , it fnllllws from Ell . I that ra te o f dm~ transport is t1in'(:tl~" pmportionul to ronce-ntrut km (Fi~, ~ ) , Fur I' Xample , rat e o f t r.lIISpo rt is i lll'rt"L~'(Il\\,lfold when conccnr rancu of dm~ is dlluhlt'll. Sta h'!.! difTt'n'utly, each lllolt'{'u !t' dHTuS('S iudl 'lx ' udelll l)"o f th e otl u-r. and tilt' sph 'lII c umot lit, s aturated. Unk-es a dm~ a ltl'rs tlw nature (If tilt' mc-mhrau e, tilt' last stat euu-ut a l ~ l a ppls-s wln-n th e uther lIlo lt'{'ul(· is a diff(' fl'nt dOl~. Both ahS('II('t., of l'l llll!X'li tio n III'tW('t'lI 11I01· t'1-'lIl('S alit ! Iaok of soll uml io n a n ' t'ha r.lt:I('risl il'S of p;L\ sin ' di ffus io ll.
Carrier·Med"lCIIod T....porI ~It' lll l mul('s are 1101 inert barm-rs: lilt .,.. han ' a s!x'!.'iali/.('(! function. ~It'lIIhr.lllt's maint ain l'ld \l{ li ll~ or n 'llIo\"iuj,t sonn- mat e rials and 'it"lIIlI'SIN illJ!; Of st'lt"i.1:in'!y n'l ai ll ill ~ \i la l substances. ~I any of tilt'S(' compounds a n ' po la r, ....-ith low lip id sn luh ili!)" )'t'l Illl'y pene-t rate membranes IlUll.·" f:l\h' r than anl i{·ip' llt'l l fnr flI...~ ..I un ,,,...
Passive Diffusion
til .. n .. ·mh........·. With P'-" r.•. ,lifT",itl", tI..· ...,,1., of 11'lU"1">t1 itlO."",""", h,..·lt1!:-· ..ilh IO.... nI r"liun . Will, (...rrio·r .n Ii.th~ l lr""'l'un . tI r.lt' ,,( Irall' I" >t1 ..Pl'.."" ~ II 1illlitjn~ ,,.J, I l,ilQ' \lt ~.
" >"t~'''t ralic>" •.
limiting Rate Carrier-Mediated Transpon Concentration
Il3
into tlu- ('1')1I1nll.')11· TPill, l. t· " a limiti lll!: value or tmnsport maxinnnn. Furthermore, ill commOll wit h otln-r (. lr rit·r-ml'i.liah 't! S)'SIt'IIIS, ~I II(.·()S(· !rdmport is n-asonably sj>t'(:i fle ami is inlrilutccl "~' ulliN slIll!olrah·s. FI"WdmJ;ts 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)", 50<J u fl h(' d m ~ is uu-iouized at th is pll. At one- pltunn luglu-r. 5 .8. 111(' roltin is to to I ill [a\ur of li lt' ioni7.l.'i.1 d mg: i.e., 10 out of II tot al parts or 9111 of till' dnlg now exists ill Ill(' ioni7.l.'t1 form . anti o nly 9'1 is IIn·ioni7.l.'t1. At Ollt' p l l uult IOWN than tilt' I'M . 3.S. Ilupt·n,'nl,.gl's ill till' ioui 7J'i.1 illlll lln -ioni7J'i.1 forms an ' 9 and 9 1, tilt' l'l 'II\'l'r~-' of those ill pH S.H. Fif.,' "n ' ').-'; Sllll\\~ d langt's in tilt' I)('n '('ul of IIn·iolli7.l.'l1 limg witll p I! for ,Ki tls of tlif· [l'n'nt 11M \"allit's. 111t' p ll r.mgt' l .u to S.Ot'n('lmlp asses values seen in th e ga...troinlestinal Irat1 .. hnth "d.IK· "'Ill 1\;I., it;· rUllu f pll Oil tI u- run-s IIf abM)'1)lioll and di strillllliun , TIl(' Iilt, I, · inlh ll' nl't' of p H 011 a mIl.' pmt" "s dt' llt'lItk hO\\'I'\'I'r, on wln-ntilt' ralt ' lim itatiun lit'S. O nly if rln- Iilllitatiun is in 1)('fIIwahility is an t'lTI't'1 nf p H 011 mh l'xpl't'tt '(l. If tI.... Iimila lioll is ill !)(.'rfUSioll, tI.... problem is nul OIW of movr-nu-nt of dnl~ Ilmlll,!!:l, lllt'lIlhmll('S and. tllt'rt'fllft" any variation ill pll is 1I 11 I ikl 'I~' to ha \'{' much t'lTt'(:1 on 1hl' mit ' p n It"{'ss, \ \ 'hen- IhI.' t'(luilihriu III lit's, III )\\l '\ x-r, is iml('1)('m il.'Ill (If wlMI pnlt''ss rutelimits II.... appn);(('I, t()\\-,m l t'Clllilih riu lIl. An :onlill,l!:ly, pI! is p n-dicn-d tn aITt'in,!!: nlt'mhr.ult' s. If t"t' n ' is a IlC 'r fusinll Iimilalioll , c!i\MIt'i"lioll (If lIlt'
117
CI-tAPTH 8
hu um l d m g am i di ffusion uf lin- unbound d r ug lh mll ~h tilt' membran e mus t occu r so raptdlythat ra tes of dd h·t'l)· and transport are t'(1J1lgt'slallt s, topi ("11 lI~('n ts , and ,!l'mso l Immd ll. li· lators], 1lI ( l\'('IlW IlI o f d m~ From till' sih' of app!i...II .l. .... .lid. " 'K'(Ml ll h' n .. ....·r..l l...rrirn ..,KI Sl iM uf 10-",. in ito .... 1'.....Ii.,] ItMM"" ... ,,1 .h llillit jl.oL'ln'illlt"Ii " ..I ..I"'''l lt i''fI. 1>i.." .I"h"u. .. l' n·""'llIi'i' .. ' " " MM·" ... "I ......"'. JI:Ill "'all , i. tI... li..... '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.start of ti M' 1"('(11111 I.·fun· ll llall~' rhilll: In 7.0 in Ill(" d,-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' an ' made, which are mpidly ("()JIvl'rt('1110 Ill(' adin' molecule. oftI'll du rin.t:: passa.t::e through the intes tinal wall. For example, absorption of Iht, polar anti hiot k amp idllill is illl'fllllplt'f(" Its sys temic dd i\l'f)' is Improved substa ntially by adlII in ish'riTl~ a ilion ' lipophilit, and permeable inactive este r prtK1m~, pivampiedliu. Tluh~ 'tlrol ys i s o f tlris ('StN wit hin tht, inn-stmal wall is so rapid that ulll~' ampicillin is t1('h'(1('11 in tht' l'i rt'ulatiun . D r-n vativr-s. such ;l\ pivampicillin. an- ~(,'l('r-dlly refem-d to as 1Jmd",1!. ~ , ' lS t1l1'y an- ph arnlill'fllc'¢lM dlly inacti ve. 1If'I Kltic Extract ion, Aspirin ( a{1:tyl sal k~..lie add) is om- of till' first Sp ltllt'lk prodrugs. It was lIlarkl'l ('11 at the tu m o f tlu- ("('lItUl)' to overcome the unpl easant taste and tilt' gast rotn tes nual irritation ass ociated with lilt' pan-n l d rug, salk ,..lie add. Aspi rin W1l~ o ri¢ nally thought to hI' inadin', I)('ing des igned to be rapidly h)"tlmIF '('l1 wi lhi n the hndy to salit"!i{' add. Only slll)';('(III('ntly was aspirin shown to he pharmacologically adiw, Y(Ot tilt" ori¢nal dt'sign wor k('11; upon ingt'stioll, aspirin. a labile es te r. is r.tpid l)' h)'tlml)·J'.t'lI, particularly hy ('.S It' fi N'S in the hw r. Ind(,,( '1I, Ilt'patk lJytl mlysis is so rapid that a siJ".(';lhlt' fraction of aspirin is {1111\l,rt('11 to salk)'!i{' aoid in a si n~I(' pa~sa!-,:(' th rough th e liver, n's ultill~ in a substantial "first -p ass d T('('I ," 1)OII-:S tllat showa suhs tautra l first-pass ('ff£'ct d uo to Ilt'p;ltk elimination art' listed in T ah lt' 9--.1. Apart [n uu th is feature, tlll'y have httle in common. TIll'" are of d iw I'Sl' chemical structu re . PI)S"l·s.~ tliffe l't' llt pharmacologic act ivitie s, am i an ' llwtaholiJ".t'l1 via a num ber of pat hways. \\1 It'l1 tilt' llwlaho lih' (S) formed durr ng tilt' first pas s tIlrtm g:h the lin 'r is les s po ten t th all the parent t1m~, tile 0 ...a1 dose is la~ef than the i.v. or t.m. dost, n-quln-d to aclik-ve tilt' ...11111' tlu-rape-uttc effect . 11 1 i.~ occurs for lIlallYof tilt" t1m ~ listed ill Tahlt' 9--3, In ~ l lll(, instances . t' .~. , i~lp mlen'nol. lu-patic extraction is so hi~h us to ('Sst'lIliall)' precludo tl\(' o rul m utt', Ih-n-. nn amount of pbunuaceuucal fonllu latioll he lps. Euher till' dnlg mu st ht· gh '('11 by a parenteral mute, o r it must 1)(· discarded in favor of another drug {'illld icl"tt" A method of l'stimaling tilt' mlll;imumlikeh· d, '('n'RS(' in oral h ina\"ailahi lit\' due to this firstp.lSS ('ff('11 is diS{'lI~S('11 in Chap. I I, Elimi;lat ioli. •
..pre
, • .,1. 9-3. .......Iv.· ..n'
H
v. Drve. lltewl~ Lew 0-1 al_v-IJ..,lIlty"'" I. D.e .. lc Ilf........_·
Alpteoolol
Hydrobzllle
NaltteXOlle
,Am,'rrptyliroe
Imipt.. ~ :4.""""!:l. 1!:1!i".U
121
CHAPTHQ
('nslln' {'Unsbh' nl and mon- t'UTll p ll·te hina\'ai bhi l i l~' or Illil}' rt'fillin' til(" dl ·\l.·lopnlt'1I1 of 1II0 rt' SPl'1..1 fil' methods for ( Iel i\"t'ri ll~ t1wS(' dnl ~s to tilt' sil t" of act tou.
Absorption From Other Sites DOl ~S mav hI,' udministe n xl to vtrtnallv unv sih- of til(' bodv. Th is is cr-rtamlv trm- of local ;lIl l'stllt'lk~ . III rt'1.'t'1I1 years then- h'L'> ill"t·.; l'()IJsi li lt' 11I1l ~. 11'('>:11 lOil\;I,.. ami bucca l (w .n i t)" ,t,> a IIw ans of ddi \'('rill~ dmj.,~ s) ""Slt·lllk-.i.lly. TIlt' IIt'W P(JI~"Pt·plidt· and pmt r-iu d m~s that an' poo rly mid (·rr.t.lkully abso rbed when ~h'(' 11 UrdU)' h,,\"(' r('('('i\"('t! parti cular .utent tou. Tr ausdr-rmul allpltcauon ha.. become popular for systemic dd i\l.·ry of small. ~(·Ilt ·I1lIl)' !ipoIlI.ilk'. pote llt molecules that n-qutrelcw Input rates 10 a(.'hie\"t' d Te(.1in ' tln-rupy. In all cases. considerarion hit.. to hl' ~H'II to the particular p roperties o f 11Il' sin- and rln- d m ~ . :'\OIlI.'t!I(']t'ss. IlnIactors i n fl uellcill~ abso rpuon fro m IheS(' sites art' li kd~· to ht' till.' same .t.. t!loS(' i n llllt'lll..'in~ ubsorptfon from tilt, oral, Lm., ami s.c. sites.
ABSORPTION FROM SOLIO OOSAGE fORMS formulation Ecpmlil)"of d m~ content (lot,S lint ~uar.lll lt't· {'flua lity u f dlk~I{·Y . TIll.' prt'S('IIt1.' u f diff i-n-nt excipients (iIlWt'tlit'llts in addition to t1 m~) alld lllimll fill1llri ll~ pmf,'l.'SM'S lIlay rt'snlt in dnsagt· forms l1mtaining rlu- S'Ul1l' dn S(' nf drug hl'1 m\i ll ~ difft' rt'lIlly i" t· it~J . 1I 1'1Il'l.' Ilnn-ason for It'slin~ for hioe quivu leuce of preparations of a d m~ iutended to bc' switd lilh!(' (p . 45 ). Gt'lll.'mlly, Iht' primary conce-rn is \\illl till.' extent of absorption . Ot:l ot. ..1(ml,," ..110,..·) I..·r,,"" "" .'1'1... ..;.." ..• fr...1i"l1 h I....·" .."."..t.... !. In t....,tr t . ",I..." tl.,... .t..li"" nl lt·· !im ih ;d"" rptio" l ((::.-. ii i, '-"r;. Iilll.· ,tml( i> in ....Iuti,.., ( n..1li"d .tI II..· "h''''l'tic." , il.· '" ..,,~- Ii"..·: ,I",,, i. ;d""..t"..1... "'" ;0.' il .Ii .", .t,, ~_ X..'i..· thai Ih. · "'..~ ,ri ~ .. r ,1 m:.: n.. ..1... >rI"...1 i. aho.ll~" r'''llltllll till" r.d... linllti"l: .It"!" in ...,Iutio.., in C,,-,,· .'\ ;11,,1... a ...,h,lm Ca....· H.
130
solid. T his explai ns why tablets. capsules. ,lIltl even sus pen sions of sll;l ri ll~ly soluhle dnl ~s an' prOlIl' to absorption problems. E\"('II if dissolutiou WN t' 1I0! tln- rate.lilllililll?; ste p and s,;ltu ralt't l solnnon at til(' abso rp tion silt' l:ou ld Ix· llI,u lllaillt'h·riak Th' p"in" will, " n ..m · i,,,lil·..h· tiK' .. IIi
, I,,· till '" ~ i'KI;'"I"""",.~"."~OIIo: i. po ·..I....1 In .. Ii-.".· ..I ..to .. r-
IN l.o.I "'...1 t~ .. ln ·"'r.cl " ,,{
-
C~
2
The maximum initial r ate of upt ake is tilt" rate of pn-sen tancn. Q ' C A ' Further, with no d ft-"(1 i\'(' im pedance to 1II000'(' II1("nl into thetissue, hl l)(1(1 and tissue (,",10 IK' "'; ('\1,'("
.. 0 .693 _ 0,693 Kp
le
"
5
IQ/VrJ
Thus, drug leaves slov. ly From tisSllt's Ihal han ' a Il i ~h affini ty (KI') fo , it an d that an.' puu rly pc'rfUst'1l. Suppose no w, tha t tilt" urte rial conceut ra tkm is mainla ilic,,
Permeability Umitation A pl:nJleahility-rdtl' limitation arise s particularly for polar dru gs diffll si n~ am ISs li~lltly knit lilXli{llJ memhram-s. as demonstrated in Fi~. 10-3 for 111(' p;.lssa~l· u f compounds into till" ce re brosp inal fluid . In th is study, till>couceutration of (';u:1J d m ~ was un-asun-d in ce reh mspinal iluid . n-latl vr - to that in plasma wate-r (unbound], wuh tillll' roll(J\\i ll~ attaiurucut and maintenance o f a constau t p lasma conccutrarion. Diffl'n.'l1l'(·S in (',lS(' of ('niT)' an' a
A
aN, (mUminlmlj 4
Kidneys
~
S
05
c 0
~
S
K,
5
5
4
c
~
0
E
~ 3
Brain
g 0,5
'"
2
~
u
0
c 0
Q ~
~
0.03
Fat
0 ~
Q ~
~
~
0 0
2
3
4
Minutes
2
0
~ ~
~
B
5
6
0 0
1
2
3
4
5
Hours
t'l lt , 10....2. I r .li,tnl.Illio" i. l"'n',-,it.u nl h·-limil... 1. tilt.' lin... til lI,at,l, . 'C! "i lih riu ,n ill Ih rt..,,,.....f .b.. .. " i;tli;
