Burckart, GJ

Ptachcinski, RJ

Starzl, TE

Venkataramanan, R

Yang, S

English

Name not available

Extraction ratio of cyclosporine in a liver transplant patient

D-Scholarship@Pitt

;:;I;~:~II~;I ~ ,..,< " \"" /~KM["~ I , I I! 'I I -xtraction Ratio of Cyclosporine in a Liver Transplant III" lient with Organ Rejection t:> IIrT ' .. , To the bditor~ clearance value compares well with the mean (:: SD) blood Cyciosporine, a cyclic polypeptide with potent immunosup- clearance of 8.4 (:: 3.6) mUminikg estimated in 10 pediatric pressive properties,' has been successfully used to prevent liver transplant patients subsequent to an intravenous jnfu-the rejection of transplanted organa such as kidneys, livers, ajon of cyclosporine.' These intravenous studiu were con-heans, and bone marrowK~ It is highly lipophilic and is dw:ted within 10 d after . transplant. It is likely that the I eliminated primarily by metabolism in the ·liver.- Recent metabolizing ability of the liver would improve with time I studies in transplant patients indicate c:yclosporiDe to be a and that one might observe a higher cyclosporine clearanc:e low-t.o-intermediate clearance drug. We had a unique oppor- ill a clinically stable patient.' " •. 'c'. tanity to directly determine the hepatic atrac:tion ratio of . From the above obsenation. it appears that c:yclosporine is this cIrui in a pediatric liver transplant recipient. . a.drug with a low-to-medium extraction ratio. In the present The patient was a 40-year-old male who underwent liver atudy, the extraction ratio wudetermined at a amcentration transplantation for at-antitrypsin deficiency. Subsequent to or 500-600 n.gImL of. c:yclosporine. The extrution.ratio of his first transplantation, he progresaeci well until 1 month certain drugs are concentration dependent. Presently, there following 51U'gery when he developed hepatic artery throm- . is no eYidence to Illggest that cyclosporine undergoesnonlin-bosia. He received a second liver 63 d after the.1irst trans-ear elimiDation kinetics in humans when admmjstved in : plant. On the day prior to the second transPlant, the liver lberapeutic dales. It should aIao be realized thaub emac-. function tests were as followa: .Jk.)jne phosphatase, 63 lUlL; tian ratio or c:yclosporiDawaa c:alculated in .,.Jfnr with : IIInlm glutamic ouloacetic tnml8Dlin 'M (SGOT), 8M lUlL; hepatic arterytbrombosia It is not known to wbatu:teDt the ,: Ie1'Um glutamic pyruvic trans·mine (SGPr), 273 lUlL; bili- metabolizing capacity or the liver will be altereliby hepatic rubin (total), 1.0 mgldL; bilirubin (direct), 0.2 mgldL. This artery thrombosis. In additioD. the effect of c:hmaic-immuno-. D~icated that the patient did not have a normally function- nppressive therapy with c:yclosporin.e and a low daM of liver. The patient did not receive any drup known to pndnisolone on cyclosporine metabolism is not bownat the lDduce or inhibit the drug-metabolizing eDZJ1II8 syatema of patMJit time. In any ~ the fact that qdosporine is the liver at any time prior to the I8CIDIId transplant. At the Primarily metabolized in the live!' and that it is a drarwith time of the study, the patient received c:yclosporine and a low Iow-to-intennediat extraction indicates that ita: cJeennce . dose of prednisolone as UnmUlUllUpplrisents, captopril for can he altered significantly by c:haDPs in tha.·iDtrinsic thetrutment of hypertension, and QBtemic aatibiotics. ... c1earam:e and blood proteiD. hind;ng and to a IIIIid18r eztent Prior to the operation, 30 mgimofsecabarbital waa.dndni.. by c:banps ill the liver blood flow. Recent Itadi8s have tered.Just prior to the removal of the first tnmaplantedliver, reported increased metabo1ism of CJdosporine bLpatienta Iimultaneolll blood samples were obtained £rom the hepatic . treated with phenytoin, phenobarbital, or mUDpin, which and portal veins. Blood samples .... kept frozen until '. are .knoWu to induce cirug-metabolizing e~ltp:Dheto-analyzed for whole blood c:yclosporiDe concentration by conazol8y which. is known to inhibit drug-met;ab01i iin .. en-HPLC. . . zymes, has also been reported to increase c:yclosporiDe,blood The bl~ was extracted using the procedure of Sa,Rhuck levels in kidney transplant patients. 13 In cam:bilion, the ~ CartIer.' Samples were analyzed using a R~IKKm C1I presentobsenationagreeswiththerecentstudiaiDdicating Cll~ E~upelcoI Bellefonte, PAl .heated .to 70"C and UV cydosporine to be a drug with low-to-intermed.Wedearance. cetectlon tmodel441; Waters Associates, Milford, MAl at 214 ., nm.. Standards were prepared in blank blood, and the inter-nal standard was cyc:losporine D (Sandoz Pharmaceuticals. Basel. S\\;tzerlandl. The mobUe phase was 6890 acetonitrile, delivered at 1.8 mUmin. Under these conditions, the reten-tion tiro ~ for c:yclosporine was 9.8 min and that for cyclospor-ine 0 \\ as 12.Smin. The CV of the analytical method was 3.95% at 600 nglmL (n - 10), The concentration of cyelospor-ine in the portal vein CPv) was 596 ngimL. whereas the he~Ptic vein \ HV) concentration was 500 ngimL. The hepatic er=:;.ction ratio was: H . E . Ra· PV-HV ep:l.t1c xtractlon tl0 - pv -= 0.161 .1 t!-.:s J;st:ent, the first transplanted liver was 740 g in wtig:'t. The hepatic blood flow inhUIDallS is 100 mLlI00 i of live:- v'eight.' Therefore, baled on an estimated blood dow or 7';0 cl.. one ~would predict a .. cyc:lasporine clearance of 119:~ r::.:L=..i:l or 7.6 IX'.Lminikg in:this patient.TFiia. predicted , . y' Y·,-', ~~"KC ~~;D::~I~~ References and Notes I: Borel. J. F.: Feurer. C.: Gubler, e~ U.; StaheiiD..- lit ABenta ActiolU 1976.6.468-475."'::;' . 2.:. Caine. R. Y.: Thiru. 5.: McMaster. P.: Craddock. G.N.; White. D.J. G.; EVan!. D. B.; Dunn, D. C.; Pentlow, B.D.l.aIacd.1918, ii. 1323-1327. ..' 3. Starzl. T. E.: Klintmalm. G. B.; Porter. K.k Iw:atauki. S.; Schroter. G. P. N. Engl. J. 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W.: Coles. . R.: 5:.awec:iti.1lM.: hoe~lerKgK: Carruthers. G.; McKenzie. N.; Si::cialr; N;R. 'Transpi.an.t. Prrx:. 1982, 14. SR9~S1K n. Bu."'t.urt. G.J.: Venkataram.aDan. R.; Griffith. B.; Hardesty. R.; P-...1C::::lnski,·R. J.; Fricker. F. J. Drq lilUU. elin. PJuum.. 1983, 17. -446. 12. La.r:;iloa. E.: Madsen. S.lAnat 1983. 2. 1031. 13. fert".aon. R.M.; Sutherland. D. E. R.; SimmolUl, R. L.; Najar-ain. r. S.1An.c1!t 1982,2,882-883. . '.--902 .,' _ -31 cf ,"harmaceutical Sciences ,- _ .-". No.. 8, August J985 ; Received AonI9. 1984. n .. ;fK~D:"D:K l~tKhr I-;";;DD;DFA;DDIDKf"Dy~DD , "'RICHARD Jrp-rACHClt.SKf :."" • -, GILSERT"J1BU;:CKAAT 'SHUIN YANG "THOMAS, E.: STAAZl. Clinical PharmaccJtinellcs laboratory SchoolS of Pham:acy and MediCIne University' of Pitts!)Urgh Pittsburgh, PA 15261 Accepted for publication May 9, 1985. " . -:- ~ . , .. . ' : ..... .' ..... ,". _ .... _--. ~--IKK;KKK~:K . .-:"....,... .... -.: .. -~KKK;K .:--,-.-..:... 

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Extraction ratio of cyclosporine in a liver transplant patient

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