10). - University of Pittsburghd-scholarship.pitt.edu/4413/1/31735062110691.pdf · 2011. 7. 14. · 'lhe objective of the present study was to oc:aprehensively examine the effect

10)..7 VOL. 64, NO.3 JUNE 1989

Research Communications in Chemical Pathology and Pharmacology

A. D'mello*, R. Venkataramanan, M. satake, s. Todo, s. Takaya, R. J. ptachcinski, G.J. am::kart, T.E. Starzl

Schools of Rlannacy and Medicine, University of Pittsburgh, Pittsblrgh, Pa 15261

*Present ackiress: Ihlladelprla COlle;Je of Fhannacy and Scierre Ihlladelprla, PA 19104

NIJmerWs clinical reports have documented an increase in t.r'cuJh blood conoentratiCl'lS of cyclosporine in transplant recipients treated con::xJ!\itantly with ketocxmazole. '!be objective of this stuiy was to elucidate the mechanism(s) un:ierlyin;J the cyclosporine-ketoconazole interaction usin;J a choledoc:::halreteros dog IOOdel.. Five male beagle dogs received a 4 nqj1cg, Lv. bolus dose of cyclosporine either alone or on day seven of a 10-day, 13 nq/Jcg/day, oral closin;J reg:iJnen of ketoc:x:rlazole. Blood sanples were collected prior .. t;o. and at predeteI1nined times for 60 hrs after the cyclosporine dose, while the bile/urine mixture was collected quantitatively for 96 boors after the cyclosporine dose. Ketooonazole decreased the systemic clearance of cyclosporine frau 7.0 ml/lninlkg to 2.5 mljlnin.lkg. '!he tenninal disposition rate constant was also decreased significantly fran 0.0794 to 0.0354 hrs-1 • Ketoc::lonaZole caused no significant charges in cyclosporine steady state volt.une of distribltion, or plasma llJ'lboun:i fraction. Ketocx:nazole did not significantly alter the excretion of cyclosporine and varioos cyclosporine metabolites in the bile/urine mixture. Inhibition of hepatic dJ:u;J metabolizin;J enzymes ~ to be the primary reasal for the ketoccnazole imuoed elevation in cyclosporine cxn::leJ rtration.

INImll.JCl'IQf

cyclosporine (C'iA) is a unique i.nm.Jnc:lsuwressant used to prevent

the rejection of transplanted organs and to treat diseases of

autoimmune origin. cyclosporine is a neutral cyclic polypeptide

oonsistin;J of 11 amino-acids (Figure 1). cyclosporine u:rrlergoes

extensive hepatic metabolism in humans and animals. '!he

biotransfonnation pathWay of C'iA is qualitatively similar in all the

animal species st::ldied. (Beverid;Je, 1982: Maurer ~. , 1984 :

441

VOL. 64, NO.3 JUNE 1989


Venkataramanan, 1988). Of the 17 suspected metabolites of aA, 11 have

been isolatecl ani identified (Maurer ~., 1984). All the identified

metabolites have the intact cyclic oligcpeptide structure of the parent

drug. Structural nalificaticms durin;J metabolism iD:lu::Je JIItIlO- am dihydraxylatim as wll as N-demethylatiext (Figure 1). Isss than 1\ of

the administered dose of aA is excreted in the bile as parent drug

while greater than 4n of the dose ~ as aA metabolites

(Venkataramanan 1985a: Wood ~., 1983). Patients ~ receive aA

nay require antifun;Jal therapy. Ketocalazole is an orally active

antifun;Jal drug. Recent clinical reports bdicate marked irx:reases in

blood t.n:u;Jh c:x:n:srtration of aA alCD;J with an in::rease in serum

creatinine in transplant recipients treatecl caxxmitantly with

ket:cc:alazole (lob:ger1St:em ~. , 1982; Fergusal ~. , 1982;

Dieperink ani Jt:)ller, 1982: l>I1ite ~., 1984). Hcwaver the

mec:bani.sa& urderlyin;J this int:eractim have oot: been OCIIpletely

characterized.

'lhe objective of the present study was to oc:aprehensively examine

the effect of ketcx::alazole at the plasma protein binii.n.J, hepatic

metabolism, ani biliary excretim of aA.

Qnicals:

Cyclosporine (samilmune Injectable - 8amoz) ani ket:cIcx:mzol.e

(Nizoral tablets - Janssen) wre p.II'dmsed frail CCIIIIIBl'Ci.al sources.

Cyclosporin 0 ani cyclosporin G wre gifts frail Samoz, Inc. other

c:hemicals ani solvents wre pm:hased frail Fisher Scientific CO.

(Fairlawn, H1) ani wre of ACS reagent grade ani HPIC grade,

442

VOL. 64, NO.3 JUNE 1989

respectively.

Stu:iy Prgtoool:

Research Communications in

Chemical Pathology and Pharmacology

The stu:iy was perfonned in five male beagle dogs ~i~ between

13.5-18.0 kg. A dvJledodlcm:et:eros was perfonned in all five dogs

awraximately six JI01ths prior to the present stu1y. '!he a::mtal bile

duct was ligated close to the c::hxrlenJm am cxxal9Cteci to the ur:i.naIy

black:ier usin;J a plastic stent. In the c:x:ntrol (base the dogs received

a 4 nqIJcg i. v. bolus dose of crA t:hrtugh a catheter placed in the

fE!IDral leg vein. In the treatment IilaSe the dogs received a 13

nq/kg/day oral dose of ket.c:x:xxlazole for 10 days. On day seven of

ketoconazole therapy the dogs received a 4 nq/1cg, Lv. bolus dose of

CiA, one hrur after the regular daily dose of ketooonazole. In both

pw;es of the stu:iy, the dogs \oIet"e fasted for 14 boors prior to am. for

foor halrs after the C'lA dose. A one week washcut period was allaNed

Intravenoos C'lA solutions \Were freshly

prepared 00 the day of the stu1y by dilutinj the cx:mnercially

available preparatioo (sardilImme'IM r. V.; sandoz Inc., Basel,

SWitzerlam) with sterile saline. Ket.occmzole was administered orally

as a suspensioo. CcmDercially available tablets (Nizoral'IM; Janssen

Fbarmaoeutica Inc., Belgium) \oIet"e crushed in a mrtar am. fornul.ated

into a suspensioo with si.q>le syrup.

Blood was sanpled before am at 0.25, 0.50, 1.0, 2.0, 4.0, 6.0,

8.0, l2.0, 15.0, 24.0, 36.0, 48.0 am 60.0 hrs after the C'lA

administration. Blood sauples were stored at -20·C pen:tin;J high

pressure liquid c::hranat:oc;JraPU.c (HPlC) analysis for intact crA. An

aliqJot of the blood semple was ~, plasma collected am.

stored at -20·C ~ HPLC analysis for intact ket:oc:xrla.zole.

443

- --- --------- ~--.------------------~. ~ - - - -

VOL. 64, NO.3 JUNE 1989


Bile/urine mixt:ure was collected quantitatively us~ a metabolic cage

in 12 hr intervals, for 96 hrs after the C'iA dose. Bile/urine sa!!ple

volumes were ueasured, ani an aliquot stored at -20'C perxii.n;J analysis

for intact C'fA ani C'iA met.al:x>lites. Bioc::hemical irxtices of liver

functioo was ueasured in all five dogs dur~ both pw;es of the sb:dy.

In vivo plasma protein birx:1in;J of C'fA was dete:tmined fran erythrocyte

partitionin;J measurerrents us~ the proaedure described by Tl:urg ~.

(1984).

cyclosporine conoentratioo in blood saDples were measured us~ a

specific am sensitive HPIC methcxi (ptadlcinski ~., 1985) while

ket.ocalazole ooncentrations were neasured by the HPIC method of Badcock

(1984). '!he metabolites of CY.A were separated us~ a high pressure

liquid dlranatcgrapric gradient elutioo system devel.cped in 0lI'

laboratory. six ether extractable metabolites were separated us~ a

solvent system oa'lSist~ of a linear gradient of aoet:aritrile am

water startin::J at 35% acetonitrile am in::reas~ to 67% acetonitrile

CNe:r 65 minItes. '!he JOObile Jilase was p.mp:rl thl:"cu;Jh the column at a

flow rate of 1.7 ml/min. '!he extractioo ani other dlranatograpric

cxnti.tions enployed were silllilar to those enployed for the analysis of

parent C'fA. since adequate quantities of pJre metabolites were not

available for cxrstruction of stardard. calibratioo plots it was not

possible to quantitate the absolute aDO.Il'lts of the metabolites.

'Iherefore, peak area ratios of each of the metabolites to the intemal

standard were calculated for each sanple. 'lbese values were normalized

for differeooes in the total volume of bile/urine mixture excreted by

the five dogs dur~ each Jilase of the sbXty. 'lbese nozmalized values

were Sllbsecp!ntl.y cxrwerted to cycl.osporine equivalents am used to

i I I

VOL. 64. NO.3 JUNE 1989


~I ~'I'

h t I' .~tII.

01, (I. "".,-" I • IO!I' til r CI!, ,til! 'cJ 'CI! ?!

til. CI. CI 01. I til. t.~. , • I ' I , • I • I '

a, .•. a • c . , - QI • C •• - <I • t: ••• 01 • C •• _ CI. I , 'I , ". .

~! ~.. II 0 , ". I~ R • C • a •• au, I R

, • I • •••• 2

DI!~!.:: :~ ~ f:~.J Dt.CI-I.Q.Q1.I·C-tII_I·(·Q1· •• Q.a

I I I I I I I I a, ! 01, ~~: q: ,CI, CI: : .. i .............. : C CI: CI!: ~

a: I 'a. a;; I D. 'R ' • • 4 R3

Metabolite other NIlIIiJer R R1 R2 R3 R.t Mcd.ificatia'l

cyclosporine H H (]f3 H H

1 Q{ H (]f3 H H

.6 Q{ Q{ (]f3 H H

11 H Q{ (]f3 H H 0

/ \ .18 H Q{ (]f3 H H (]f (]f-Cll2 of IJ.

P E t;

11 H H H H H

.u hydxaxylated am. N-demethylated derivative of cycl.osporine

Figure 1. structure of cycl.osporine am. its metabolites.

o:::apm! the effect of ketoccnazole en the metal:lolic profile of CYA.

M:del imEpeldent }i\annacokinetic parameters for CYA includinq the

teminal dispositien half-life (Tl/2)' total body clearance (CL),

intrinsic clearance (Clu int), am steady state volume of distribltien

VOL. 64, NO.3 JUNE 1989

Perrier, 1982).


Differences in JOOdel i.n::\epement ~c

parameters between the control and treatment groups 'WIIE!l"e evaluated

us~ the Sbldents paired t-test at a significant level of 0.05.

~ CI ..s. c ~ e c • u C 0 u ~ 0 0 iii • .s 0 Q. .. 0 u ... u

10000

lDOD

100 . 0.0 •• D 1.0

I 1Z.0

i i 11.0 20.0

TIm. (Mrs)

I 201.0

i lI.O

i 35.0

Figure 2. Cyclosporine blood CXllCel'ltratial versus time profile in dog '4 before (0) an:! dur~ (0) ket:ocalazol.e treatment. Each dog received 4 nq/J<g of cycl.osporine as an int.ravencuJ bolus injectial.

Figure 2 shews the CiA blood CXlk:leIttratial time profile before an:!

durin:} ketcocnazole treatment in dog l'IJIIiler 4, \r4lile Table 1 SUIIIMrizes

the effect of ket:ocalazole al CD. dispositial in five dogs.

Ketcx:x:nlzole caused a significant drecreI!Ise in the systEmic clear:an::l8 of

VOL. 64, NO.3 JUNE 1989


Table 1

Mean cyclosporine Iilannaookinetics in five dogs before an:l durirn ketocxl'lazole tI"eatmrt:

Treatment, Mean ± S.D.

Parameter cycJ.osporine cycl.osporine (units) Alooe + I<et:ocx:n1zole

1) Dispositioo 8.7a 19.5 Half-Life (hrs)

2) "2 (halrs-1) 0.0794 ± 0.033 0.0354 ± 0.022

3) o.mulative ADnmt 0.19 ± 0.10 0.40 ± 0.25 Excreted (ng)

4) Clearance 7.0 ± 3.6 2.5 ± 1.5 (ml./mi.n,IJ<g)

5) Plasma Free 0.090 ± 0.05 0.16 ± 0.10 Fractioo

6) Intrinsic 69.70 ± 10.0 6.72 ± 1.8 Clearance (ml/lD.inlng)

7) steady state Volume 4.0 ± 0.8 4.4 ± 1.6 of DistribJtioo (IIJcg)

~cmean

P Value

0.005

N.S.

0.013

N.S.

0.001

N.S.

CiA fran 7.0 ml,lmi.n,l.kq to 2. 5 ml/Ini.rVJaJ with a pxcportiooate increase

in its half-life fran 8.7 to 19.5 hoors. Ketoc:a1azole also caused a

narked decrease in C'lA intrinsic clearance fran a mean of 67.7

ml/Ini.rVJaJ to 6.7 ml.,/lnin/J<g. 'lbere was no statistically significant

c:han:.Je in CiA plasma protein or its steady state volume of

ctistrib.Itioo •

Ket.oc:x:I'lazole caused a 17-56\ decrease in the levels of three of

the six CiA mtabolites Crable 2). Si:aultanecA.ls, am prOOably

441

VOL. 64, NO.3 JUNE 1989

21

18

1

17

13

8


Table 2

Effect of ketcxxmzole en the 1lf!P!lnlic profile of cyclosporine in dogs

Treatment, Mean ± S.D.b,e

cycl.osporine cycl.osporine Alene + Ketooc:nazoled

2.4 ± 1.1 3.7 ± 1.7

0.44 ± 0.2 0.55 ± 0.4

1.7±O.5 2.2 ± 0.7

0.92 ± 0.3 0.77 ± 0.3

2.7 ± 1.2 1.S ± 1.1

1.1 ± 0.3 0.56 ± 0.5

~er to Figure 1 for detailed structure of the met:aJ:x)lites.

~- 5

OValues are expressed as cyclosporine equivalents.

dtkna of the parameters are statistically different (p < 0.05).

oc:.IIpE!llSatory increases ~ d:Jserved in the levels of metabolite

f'ILIIIi)ers 21, 18 ani 1. However, ncne of these c:har¥;Jes loIere

statistically significant prdlably as a ca'lSE!qIlellOe of the variability

in the data.

Figure 3 sha.Is the Jcetocalazole plasma (Xn::entraticn-time profile

in dog 1 en day 7 of the treatment pericxl. Peak plasma ccn:Jel'ltratioo

of 9.3 J,Ig/Inl was readled between 2 to 3 hours after the oral dose.

VOL. 64. NO.3 JUNE 1989

10

--~ CI u

..s. c 5 ~

~ c • u C o

U o E .. o a: • ] 2 o c o u o .. ~

, I

0.0 1.0 I

2.0 I

3.0


1 I i i

4.0 5.0 c.o 7.0 1.0 '.0 10.0

TIm. (hrs)

Figure 3. Ket:occm.zole plasma <XIlOe11tratioo-time profile in dog #1 on day 7 of a 10 day 13 l!g/1<g/day oral dosirg :regimen.

DISaJSSICN

Ket:oconazole is a known inhibitor of microsaDal. enzymes in the rat

(Niemegeers ~., 1981; Sheets am Masal, 1984; Meredith ~.,

1985) am humans (Brown~., 1985; rBneshmen:i ~., 1983). Recent

st:uties in man have shewn that ketc::Icxnazole has no effect CXl

theq:hylline clearaooe whereas the dnJ:} decreases chlordiazep:ncide

plasma clearance leadirg the authors to cx::nclu:ie that ketooonazole

inhibits at least one subset of the hepatic mixed f'llrx:tiCXl oxidase

systen (Brown et al., 1985) • CoadministratiCXl of ketooonazole

VOL. 64, NO.3 JUNE 1989


irx:reases the serum C'iA cx:.noentrations in transplant patients

(lomgeust:em ~., 1982; Dieperink ani ~ller, 1982; White ~.,

1984: GuDbleton et al., 1985). Recently the interaction of C'iA ard

ketoocnazole was sb.xtied in mice (Amerson ard Blaschke, 1986) • A

significant increase in the half life ani a reduction in the cleararx:e

of C'iA was ci:lseIvecl in these arWna1s. F\lrther stu:iy by the sane graJp

of investigators documents potentiation of the ~ive effect

ani toxicity of C'iA in mice reoeivin;J ketcx:x:rlazole (An::lersal~.,

1987) • However the stu:iy was c:::orrlucted in two separate groJpS of

animals ard the ~ of large interin:li.vidual variations in the

kinetics of C'iA ooo.ld potentially influence the conclusions of the

sbxly. siIxJe C'iA plasma protein bi.rdin:J was not detennined in these

animals, the actual medlanism(s) responsible for the d:Iserved decrease

in the total clearaoce ooo.ld not be detennined.

In the present study, the sanv:! animals \olere used in the centrol

ani treat:nent tnase of the stu:iy. studies were romucted in dogs with

c:holedoc::houretero. 'lhi.s enables carplete rollection of bile ard

the urine for the quantitative detennination of C'lA ard its

metabolites. '!be mean cleanm::e, plasma protein birdin;J, ard half life

of C'lA in these dogs was similar to what has been reported in the

literature (Venkataramanan ~., 1987). 'lhi.s inticates that

c:holodedlo.lreteros had no significant effect on the dispositioo of

C'iA. '!be effect of cholodectlalreterostany on the clispositioo of

ketoocnazole was not examined in this stu::ly. '!be extent of inhibitioo

of dJ:ug metabolizin;J enzymes is expected to be a function of the

cx:n::entratioo of the inhibitor. '!be mean peak ketocx:lnazole plasma

cx:n::entrations of 13.1 J.IC1IlIIl that was observed in the five dogs in this

450

VOL. 64, NO.3 JUNE 1989


stldy was CX1IpU'able to that reported by Baxter ~. (1986)

inllcat.:irg that c:holedoc:hc:met:ero prci)ably had a minimal. effect on

the disposition of ketoconazole in these an.i.mal.s.

Ket:oc:xI'lazole treatment resulted in a significant decrease in the

intrinsic clearance of C'lA in dogs. A stldy in human liver microsanal.

i.rx:ubates has shcwn that ket:cxxlnazole inhibits the metabolism of C'lA.

A Michaelis-Menten plot of the data inllcated a mixed type of

inhibition (Mauer, 1985) • Pretreatment with ketocx:nlzole prOOably

inhibited the oxidative enzymes respaasible for C'lA metabolism which in

tum aocnmts for the ci:lselved decrease in its intrinsic clearance in

the five dogs. IacJt of artf significant difference in the anamt of

parent C'lA am various metabolites excreted in the bile/urine mixture

durin; the t'NO different pmses in:iicates no selective inhibition of

artf specific pathways of C'lA elimination by ketocx:nlzole in dogs.

Earlier stuiies have ~ that ketcoonazole is a potent am

specific inhibitor of N-demethylase activity in humans am animals

(Brown ~., 1985: Sheets am MascI'l, 1984: Meredith ~., 1985).

Ket:oc:xI'lazole treatment has been asscx::iated with silent am

syuptanatic hepatic reactialS. '!he effect of ket:cxx:r\azole on the liver

rarges fran asyaptanatic transient elevatioos of serum transaminase or

alkaline }ilcsPlatase to potentially fatal aaIt:e necrcsis, ani may ocx:ur

at artf time durin; ketcccnazol.e treatment (Lewis ~., 1984).

cycJ.osporine clearance has been shewn to be i:Dpaimd in patients with

liver disease (Venkataramanan ~., 1985b) am in dogs with

experimentally imuced hepatic dysfunction (Takaya ~., 1987). It

is therefore possible that the decrease in C'lA clearance durin;

ketoca'lazole treatment cxW.d be partly due to hepatic injury associated

451

.=--- ' - >

VOL. 64, NO.3 JUNE 1989

with c::hrarlc ket:cc:a1azole therapy.


HoWever, bioc:hemi.cal indices of

liver f'Ur¥::tioo reveal that ketocxlnazole treatment caUSEd 00 d'laJ'9! in

the fur¥::tiooal integrity of the livers of the animals (data not shewn).

'lberefore the decrease in C'iA clearance durin; ket:cx::alazole therapy is

primarily due to ketocanazole i.rmJced inhibitioo of the oxidative

enzymes respalSible for C'iA uetabolism.

In cxn:llusioo, the results of this investigatioo daoonstrate that

ket:ocx:I1azole decreased the systemic clearance of C'iA probably as a

~ of an inhibition of C'iA metabolizin; enzymes. Ket:ooooazole

caused 00 c::har¥3e in the distrib.Itioo of C'iA in dogs. si.roe C'iA is a

10117 clearance ciru3' in dogs, a decrease in its intrirlSic clearance woold

lead to an increase in the coocent:ratioo of the llJ'lba.ni,

pw:uacologically active species. A similar medlanism may also be

rE!SIXIlSible for the :in::reased JlE!Ifu'otaxicity d:lselved in transplant

recipients treated cx:n:x:mi.tantly with ketcx:la1azole.

ArDersal, J.E., M:lrris, R.E. an::i Blasd'lke, T.F. (1987). Ket.oca'lazole p:Jt.entiates cyclosporine ~ioo am toxicity in mice. Transplant. Proc. 19, 1267-1268.

Amersal, J.E. am Blasd'lke, T.F. (1986). Ket:oc:cnazole inhibits cyclosporine metabolism in vivo in mice. J. Rlannacol. Exp. '!her. 236, 671-674.

8adcoc:k, N.R. (1984). Microdet:enninatioo of ketoconazole in plasma or serum by high perfonnance liquid c:hrana~. J. Chrcrnatogr. 306, 436-440.

BaXter, J.G., Brass, C., Sdlentag, J.J. am Sl.au;Jhter, R.L. (1986). Rw:macok.inetic:s of ketooonazole administered int.ravenoosly to dogs am orally as a tablet an::i solutioo to humans am dogs. J. R'lann. Sci. 75, 443-447.

Beveridge, T. (1982). Rlannacokinetic:s am metabolism of cyclosporin A. In D.J.G. White (ed.), Cyclosporin A, Elsevier BiaDeClical Press, Oxfotd, Erglan::i. pp. 36-44.

452

"nn

VOL. 64, NO.3 JUNE 1989


Brown, M.W., Maldonado, A.L., Meredith C.G. ani Speeq, Jr., K.V. (1985).

Daneshmerxl, T.K., Waxnoc::k, D.W., Ere, M.D., Jeilnsal, E.M., Parker, G., Rid'lardsal, M.D. am Rd:lerts, C.J.C. (1983). M.ll.tiple dose pharmaooIdnetics of ketoc:D1azole am their effects on antipyrine kinetics in man. J. Antimicrd::l. Ole!!oother. 12, 185-188.

Dieperink, H. am Iwbller, J. (1982). Ket:ocxrlazole am cyclosporine. Ianoet 11, 1217.

Fe.rgusal, R.M., SUtherlani, D.E.R., 5i.Imals, R.L. am Najarian, J .5. (1982) • Ketoconazole cyclosporine metabolism, and renal transplantation. Lancet 2, 882-883.

Gibaldi, M. am Perrier, D. (1982). M.ll.ticxmpartrnent lOOdels. In Rlannaookinetics. pp. 45-112.

Q.mbletoo, M., Brown, J .E., Hawkswcrth, G. am Whiti.n:}, P.H. (1985). 'lhe possible relationship betwen hepatic dnJ;J metal:x>lism ani ketoconazole enhancement of cyclosporine nephrotoxici ty. Transplantation 40, 454-455.

Lewis, J.H., Zimrerman, J.H., Benson, G.D. ani Ishak, K.G. (1984). Hepatic injury associated with ketcx::onazole therapy - an analysis of 33 cases. Gastroenterology 86, 503-513.

Maurer, G. (1985). Metabolism of cyclosporine. Transplant. Proc. 17, SlWl 1, 19-26.

Maurer, G., l£x:lsli, H.R., Schreier, E. am Keller, B. (1984). Dispositioo of cyclosporine in several animal species am man. struct:ural elucidation of its metal:x>lies. DnJ;J Metab. Dispos. 13, 156-162.

Meredith, c.G., Maldonado, A.L. ani Speeg, Jr., K.V. (1985). 'lhe effect of ketoconazole on hepatic oxidative dnJ;J metabolism in the rat in vivo ani in vitro. Drug Metab. Dispos. 13, 156-162.

foa:genstem, G.R., Powles, R., ROOinsal, R. am ft::Elwain, T.J. (1982). cycl.osporine interaction with ketoocnazole am mel.(ilalan. Lancet 2, 1342.

Niemegeers, C.J .E., !.evra1, J .C., Awalters, F. am Janssen, P.A.J. (1981) • Inhibitioo am :in:luc:tioo of microsanal enzymes in the rat. A cx:mparative study of foor antimycotics: lIIi.cxI1azole, eccnazole, clotrimazole, am ketoconazole. Arch. Int. Rlarmaoodyn. 25, 26-38.

PI:.a<:b::i.nsk, R. J ., Venkataramanan, R., Rosenthal, J. T., a.u:ckart, G.J., Taylor, R.J. ani Hakala, T.R. (1985). cycl.osporine kinetics in renal transplantatioo. Clin. Fhannacol. 'lher. 38, 296-300.

VOL. 64, NO.3 JUNE 1989


Sheets, J.J. an:i Mason, J. I. (1984). Ketcccnazole: a. potent inhibitor of cytoc::hrane P-450 deperdent cl.r\.q met:alx>lism in rat liver. DJ:u;J Metab. Dispos. 12, 603-606.

Takaya, S., Zaghlool., I., lwatsuki, S., stanl, T.E., Noguchi, T., ChDori, Y., Burckart, G.J., Ftac::hcinski, R.J. an:i Venkataramanan, R. (1987) • Effect of liver dysfutd:ioo on cyclosporine pw:maookinetic:s. Transplant. Proc. 19, 1246-1247.

~, A.H., Sirois, G., D.ll:le, L.M. an:i McGUveray, I.J. (1984). CcIIparison of the erythroc:yte partitiarln} method with t'NO classical methcx1s for estimatin:J free dru;J fractioo in plasma. Biqi'lann. DJ:u;J Dispos. 5, 281-290.

Venka.taramanan, R., wa:rq, C.P., Hablc:ky, K. , Ftac:hcinsJd, R.J., an-ckart, G.J., Koneru, B., Baker, R., Todo, S. an:i Starzl, T.E. (1988). Species specific cyclosporine met:alx>lism. Transplant. Proc. 20, 680-683 •

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10). - University of Pittsburghd-scholarship.pitt.edu/4413/1/31735062110691.pdf · 2011. 7. 14. · 'lhe objective of the present study was to oc:aprehensively examine the effect