BURCKART, GJ

IWATSUKI, S

NOGUCHI, T

OHMORI, Y

PTACHCINSKI, RJ

STARZL, TE

TAKAYA, S

VENKATARAMANAN, R

ZAGLOUL, I

English

PubMed

D-Scholarship@Pitt

Experimental Study About the Influence of Liler Dysfunction Cpon Cyclosporine Pharmacokinetics S. Takaya, S. Iwatsukl. TE. Starz; I. Zag,oul T. Noguchi, Y Ohmon, G,J. Burckan R.J. mtachCfnp~i and R. Venkataramanan T HE cobnib~q malabsorption and marked variability in cyclosporine (CsA) absorption and metabolism makes CsA therapy difficult in orthotopic liver transplan-tation. Alternations in the hepatic function would therefore be expected to change the pharmacokinetics of CsA. We have studied changes in the kinetics of CsA in two types of hepatic impairments. 70(k hepatectom~ and complete bile duct ligation in dogs.: In the present study. we further in\'esti-gated the inftuence~ of various degrees of liver dysfunction upon CsA pharmaCOkinetics b) using those two types of liver-impaired canine models: the degrees of dysfunction \\ere evalu-ated by indocyanine green (ICG) kinetics to quantitate hepatic functional resen·e. METHODS The pharmacok,nellcs of CsA were studied in 20 mongrel dogs after TM~ hepatectomy or complete bile duct ligation as models of liver dysfunction. Chanl!cs in liver function were monitored by serial measuremenL< of serum bilirubin. the muimum remo"al rate II(,G·R_,l. and the plasma disappearance rale constanl IfCd·~ 1of leG a~ a hepalIC functional re~erve al Iw'O d~ (o ~ or <.0 mg 'kg) before and afler surgloI;all~ induced liver Impairments.;" C,A, " .. as admlnJ5Iered to dogs al ellher ~ mg kg for ;.0 10 fK~ hour~ fntrayenousl~ (IV I or I ~K~ m~ 'kg or"lf~ (POt on t~Do scl'araLt occas,lon; each ~eek after Ihe operation for 4 ~ceks Blood sample5 were obtained from Juguiar veins JUSI beiore and 025. 0.5. I. 2 . .3.4 6.8, !:. I b. and 24 hours after IV admlnlSlralion and 31 I. 2. 3. 4. 6.8. 12. lb. and :4 hours after PO adming~tralion (sA Fro", 1;'1' D'par/",,", of Su'guJ, L'nHUSI/\ of Pili." burglr Hl'allh ('tn/l". Add,l'SS rl'p"nl "qUI'SIJ 10 S Takal'o. MD. F,r.'1 Deparlmrnl of Surgtry. HITo.<akl Un/vl''!m School of Ml'dlciM. 5 Zaij,,-c/ro. Hirosald 01.1', Ao",orl Prt/I',-11.1'1'. Japan 036 C 1988 b.' Grunt' & S"a/lon, Inc O(U 1-/345/8Ilj2001-I056S03.00/0 conccmra 110m were determined by high· perl ,ormance uld chromalography (PHLC) as Ihe parent co~n""II~~ CsA from whole blood. RESULTS peyDent~ percent hepatectomy crealed nificant liver dysfunction. and these impairmenl subjects recovered slo .... i~ I Fig I ICG-R", •• t~R reduced by RTKTD~ ~ ?J (mean::. SD). and ICG-K \\as redtlced 61.3::. 9Y;; thefirst ..... eek after theoperat The systemic clearance (CLs) of 1\ C~A \.\ reduced by 43,99; !: 8.2SC. but later the reco\ered rapldl~K There ..... a!> a signifi prolongation of the lerminal half-life of CsA only in the first week. Ho .... ever. steady-state distribution volume of 1\' C .....as not significantly different afler hepatectomy .due to too much variability. percent bioavailability of PO CsA " reduced by 26.4% !: 14.8% (P < .05) the fi ..... eek. and later it had recovered to .... ithin t normal range. After hepatectomy, ~ signIfi-cant poSit i\'e correlation was obsened be-tween ICG-Rna. and the CLs of 1\ Cs-\ (r_ KS~K P .' .0 II. Also a SIgnificant negatl\C correlation was observed bet ..... een serial ~erum bilirubin level5 and the percent bioavaliabiilty (R = -.67. P < .0 I), However. no ~ignificant correlation was observed bety.een seriai sen.i1Ti bilirubin levels and the CLs of IV C~-y Bile duct ligalJon also Induced another type of liver Impairment (Fig 2 L ICG- R"",. was reduced by ~9 I E~ = 12,SS( the seconc yyee~ and 4RKRE~ ::. 9.9SC the third week after the operation. Durrng the same periods. the CLs .... ere reduced by 24.3% !: 13.0C;} and PSK1~ : TK9~K respectively: the area under the curve (ALT) of PO CsA was reduced by S9K9~ :: 10.7t;; and 60.8% = 15.1 ~K respectivel~K The percent bioavailability was reduced b~ 154 T,.nsplMlUltlon ProceMjngs. Vol XX. No 1, Suppl 1 (February!. '988. PI' , 54-1 se uenee of Lhe trmaeokinet' r , les ' Ohmofl, GJ B urCi(a'1. RESULTS nt hepatectom\ . f - created ' ., unction. and Ih "I' r ' ese ~ :' ,ec\)\'ered slo\\ly ( tuu ... ed b\ '-'''''' ~d gCd-~ ~~~D ;~d~ ,SI v.eek after the cance tCl!» of IV C t',r b sA :: <"-'. ut later the There v. a' a sl'g , , " nl '''', terminal half-life of tlrst week Howev . , er, tlutlOn volume of IV 'ltly different after .) too much variability bility of PO CSA' : 14,8% (P <05) the ad recovered to v.ilhin :r hepatectum,. a 1..1110n "Da~ observed '" the Cl, of /\ CsA (r 'u a slgnltJcam ne -; ed bet v. een 'enal , lle percent bloa vaila i Hov.evcr. n0 SII!n' ~y ed bet v. cen sen;1 he Cly, of IV CsA, :f~l induced another t I Fig 2) ICG-R 1 ~ or- mu ; _.<'.r the second . :h(: third "'eek after ~K ~ame periods. the '; :: I 3 ,Dc;; and 36.1% t ,t: area under the ~~ redUced b~ S9K9~ t '11,. respectivel\'. The Ity was reduc~d 155 co.. 1M~ Htp.t.ctom. , rat. SO\ 100 ~t ,-I -co~~:CCtrl::-i ----:,,-,, ~""D:D-e-D ---:-~rK-: -".-•• ----:cP-reKKgK~-.. -,-. ----KKIKKf-~ ..... ~-.. -. -• IS.tir; the second week and by '3.,.('., ..... ~K:KKK t I Uc; the third week after bile duct _I11III" HO'o\e\er no significant negative cor-,,'';:'-__ was observed between serial serum ~~"11K"" k\els and the rercent bioavailability bile duel ligation. DISCUSSION is extensively metabolized and elimi-in the bile. but analysis of bile by HPLC XA.-.PICS that b~ than 1 c;r of the administered i<Di!1Ki~I;fffff~ of CsA i~ secreted unchanged in the urine. Therapeutic drug monitoring of the CsA-treated patient i!> necessary because it is difficult to ::!ssess interindi\'idual variations in CsA absorption. distribution. metabolism. and elimmatlon. Actually. in liver transplant patients. it is much more difficult to establish near-basal values and the steady-state condi-tion because the liver is the major site of CsA metabolism. Kahan 6 reported that patients with impaired hepatic function cleared the drug one third more slowl~K thereby leading to an increased ALT from a demographic analy-f"y~f~K--------~~--~--~--~~~~~~-------mreo~ Flrll 'wee. S.cond ", .. It Thud' "'HI Fount: _I Fig 2. Changa. in pareent decra •• ing rata. of hapatic functional ... arva and kinatic. paramata .. of C.A atta, com-plata bila duct ligation. ", •• lts .It., opernlOn 156 sis using radioimmunoassay (R I A). However. because the primary metabolites of CsA do not have signIficant immunosuppressant ac· tivity in animal~ and have not been tested in humans ~ and because the deterioration of hepatic function secondary to rejection or hepatic thrombosis frequently produced a dis· proportionate me in the RIA blood concen· tration. the use of RIA in the setting of altered hepatic function grossly underestimates the required CsA dosage to achieve the usual CsA parent compound level' I n our experiments using the HPLC method of whole blood for the measurement of the parent compound. on the first week the hepatic dysfunction created by hepatectomy produced a 44Cff reduction of the CLs of IV CsA and a 15) o/r prolongation of the terminal half-life (7.65 v 5.06 hours as control). This suggested that the interdose interval should be prolonged one half longer than that for the normal hepatic functional group. TAKA 'vA Ei AJ. The asses:.ment of the hepatic dysfunction influence on (sA kinetic~ was reported bv uSing elevated ~erum bil iru bi n leve\s.9.lo In Ou'r data. significant negative correlation wa~ observed between serial serum bilirubin levels and percent bioavailability following hepatec. tomy. However no significant correlation \\as observed between serial bilirubin levels and the CLs of IV CsA. Furthermore. in complete bile duct ligation. no significant negative cor. rela tion was observed a mong the serial serum bilirubin levels. the percent bioJ\·ailabilit\. and the CLs. . These data demonstrate that liver impair. ment significantly influence~ the pharmacoki. netics of CsA. by not onl) creating changes in intestinal absorption but also in hepatic metabolism. Safe and effective therapy \.\ill require an improved understanding of how CsA pharmacokinetics varies with the degree and cause of hepatic dysfunction. REFERENCES I. Takaya S. Zaghloull. I ... atsuki S. et al: Transplant Proc 19:1246. 1987 2. ~oody FG. Rilc.kers LF. Andrete JS: Ann Sur! 180592.1974 3. Mlzumoto R. Kawarada Y. Yamawaki T. et al: Am J Sur! 131 768. 1979 4. Paumganner G. Probst P. Kraines R. et al: Ann NY Acad Sci 170: 134. 1970 5 Venkataramanan R. Starzl TE. Yang S. et al: Transplant Proc 17:286. i 9U~ 6. Kahan BO: Transplantation 40:457.1985 7. Follath F. Wenk ~K Vozeh S. et al elin Pharmacal Ther 34638. 1983 8 Burckart G. Starzl TE. Williams L. et al Trans· plant Pro.: 17:1172. fnU~ 9. Ycc Gc. henned~ ~pK Storb R. et al Blood 64127 1 .1984 10. Hows JM. ChiPPing m~1K Falrhead S. et a: Sr J Haematol 54:69.1983 

EXPERIMENTAL-STUDY ABOUT THE INFLUENCE OF LIVER DYSFUNCTION UPON CYCLOSPORINE PHARMACOKINETICS

Takaya, S

Iwatsuki, S

Starzl, TE

Zagloul, I

Noguchi, T

Ohmori, Y

Burckart, GJ

Ptachcinski, RJ

Venkataramanan, R

Name not available

Experimental study about the influence of liver dysfunction upon cyclosporine pharmacokinetics

http://d-scholarship.pitt.edu/4252/1/31735062130160.pdf

EXPERIMENTAL-STUDY ABOUT THE INFLUENCE OF LIVER DYSFUNCTION UPON CYCLOSPORINE PHARMACOKINETICS

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