Oral absorption of cyclosporine was studied in dogs with and without bile diversion. Blood and bile cyclosporine concentrations were determined by a high pressure liquid chromatographic method. The absorption of cyclosporine was signficantly impaired (p < 0.05) in dogs with bile diversion. Bile and bile salts appear to be essential for the absorption of cyclosporine

Burckart, GJ

DilizPerez, H

Ptachcinski, RJ

Schwinghammer, T

Starzl, TE

Van Thiel, DH

Venkataramanan, R

PubMed

Name not available

Effect of bile on cyclosporine absorption in dogs

D-Scholarship@Pitt

\ I VOL. 53, NO.1 JULY 1986 \. Research Communications in ~ Chemical Pathology and Pharmac logy EFFECr OF BILE ON CYCLOSPORINE ABOORPrIOO IN DOOS c Raman Venkataramanan*, Hector Diliz Perez**, Terrence Schwinghammer*, Gilbert J. Burckart*, Richard J. Ptachcinski*, David H. Van Thiel**, Thomas E. Starzl** *Clinical Pharmacokinetics Laboratory, School of Pharmacy and **Departments of Surgery and Gasteroenterology, School of Medicine University of Pittsburgh, Pittsburgh, PA 15261 Abstract oral absorption of cyclosporine was studied in dogs with and without bile diversion. Blood and bile cyclosporine concentrations were determined by a high pressure liquid chromatographic method. The absorption of cyclosporine was signficantly impaired (p < 0.05) in dogs with bile diversion. Bile and bile salts appear to be essential for the absorption of cyclosporine. Introduction The use of cyclosporine as an immunosuppressant has resulted in improved graft and patient survival following liver, kidney, heart and bone marrow transplantation (1-4). However, the various factors that influence the pharmacokinetics and pharmacodynamics of cyclosporine have not been completely characterized. The kinetics of cyclosporine are highly variable between patients and within a patient over a time period (5). In particular liver transplant patients present a unique challenge in the optimization of immunosuppressive therapy with cyclosporine (6). Recently, Andrews et al (7) reported significant increases in the trough blood cyclosporine concentrations in liver transplant patients following clanping of the T-tube inserted into the bile duct. A marked reduction in the daily dose of cyclosporine was required in order to maintain the desired trough blood concentrations in these patients. Since very little unchanged cyclosporine is excreted in the bile in liver transplant patients (9), enterohepatic recirculation cannot explain the influence of bile diversion on cyclosporine blood concentrations. Increased absorption of cyclosporine in presence of bile is most likely responsible for such an observation. We report the results of a study to quantitate the effect of external biliary drainage on cyclosporine absorption in dogs. Materials and Methods Four male mongrel dogs weighing between 17.3 to 24 kg were used in this study. The animals were fasted overnight but were allowed free access to water at all. times. Food was withheld fran the animals for at least 4 hours following drug administration. The dogs received 20 mg/kg of cyclosporine (Sandimmune, sandoz Inc., NJ) orally on two separate occasions. DUring phase 1 (control) the drug 137 ----~-------... ,- :.- ." .... ~-. :~--.. .~' .. -.... ~ . VOL. 53, NO.1 JULY 1986 Research Communications in Chemical Pathology and Phannacology was administered to the dogs with an intact biliarY system. Phase 2 (biliary diversion) studies were carried out in the same group of dogs following the insertion of a cannula into the bile duct to exteriorize bile drainage. The dogs were allowed to recover for at least 4 days following surgery prior to the second phase of the study. Blood s~les were obtained in heparinized tubes at 0, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours following drug administration during each phase and analyzed for unchanged cyclosporine. cyclosporine concentrations in whole blood and bile were analyzed by a high pressure liquid chromatographic assay (9). Terminal disposition rate constant (A z)' area under the blood concentration versus time curve from time a to 24 hours (AUC)~_and time 0 to 00 (AUC)~ were calculated according to standard techniques. A paired T-test 0 was used to determine the significance of any differences in the AUC I S between the two phases. Results and Discussion Our study design was such that each dog served as its own control. The blood concentration versus time profile of cyclosporine in dog i4 pre and post bile diversion is shown in figure 1. The blood level of cyclosporine during the biliary diversion phase were considerably lower when compared to the levels obtained with intact biliary system. -.. Figure 1. Blood cyclosporine concentrations as a function of time following oral administration of 20 rng/~g of cyclosporine in dog '4 with intact bile duct and (0 ) with biliary diversion (b. ). The mean (+ S.D) peak blood concentration of 1235 (+325) ng/rnl observed during the control phase was significantly (p < 0:05) higher compared to the peak concentrations of 273 (+88) ng/rnl following biliary diversion. Though the mean time to peak-blood concentrations tended to be longer in the dogs with biliary diversion (4.5 hours) when conpared to the control dogs (3.0 hours) the differences were not statistically significant. The mean (.:t SO) disposition· rate 138 VOL. 53, NO. JULY 1986 constant signi.fi~ (+ 0.041: lIfe was (+ S.D) I 2943 + i (+ s.Di 1 3151 (.:t -Table 1. Effect 0: (D 1 41 2 4' 3 3~ 4 4i Mean 4· S.D. a(AUC (B: ~or ~OJ '!bis dit phase wa were car. adminis CYClospor similar I less tha the diff( of abso: cyclospor to the c results : cyclosPC)l Our cyclOSPOl of lipid, Imunications in I Pharmacology . Phase 2 group of e duct to ler for at se of the t 0, 1, 2, nistration bile were 3.ssay (9). the blood (AUC)A and :echni~es. lce of any 3.S its own yclosporine Ire 1. The phase were .. ith intact :ion of time le in dog t4 ) . (+325) ng/ml 0.05) higher ml following mcentrations 1 (4.5 hours) 'erences were osition rate VOL. 53, NO, 1 JULY 1986 Research Communications in Chemical Pathology and Pharmacology constant of 0.111 (+ 0.027) hours-l during the control phase was not significant (p < 0:1)5) from the disposition rate constant of 0.100 (+ 0.041) during the biliary diversion phase. The harmnic mean half lIfe was 6.2 hours in phase 1 and 6.9 hours in phase 2. The mean (+ S.D) (AUC)~ was 11293 ±. 2611 ng.hr/ml during the control phase and 2~43 ±. 734 ng.hr/ml during the bilialf diversion phase. The mean (+ S.D) AUC'" was 12679 + 2386 ng'hr ml during control phase and was 3351 (±. 7559 ng'hr ml-1-during the bile diversion phase (Table I), Table 1. Effect of Biliary Diversion on cyclosporine Bioavailability in Dogs Dog (AUC)~ (AUC)~ % Relative t Dose Control Bile Control Bile Bioavailabilitya Diverted Diverted (mg) (ng'hr'ml-l ) b c 1 480 8456 3751 10732 3972 44 37 2 450 9717 2141 12499 2464 22 24 3 350 13199 3339 14631 3985 25 27 4 480 13800 2540 14853 2981 18 20 Mean 440 11293 2943 12679 3351 27 27 + + + + + + + S.D. 64 2611 734 2386 755 10 6 a[AUC (Bile diverted)/AUC (Controll] x 100 bBased on (AUCl~ values ~ on (AUC)~ values This difference in the AUC between control and the bile diversion phase was significant (p < 0.05) and independent of whether AUC""s were coopared or the (AUC)A'S were cOIrpared. Less than 1% of ~e administered dose of c~closporine is excreted as unchanged cyclosporine in the bile in dogs following a dose of 20 mg/kg. The similar half lives observed during the two phases and the presence of less than 1% of the dose as cyc10sp0rine in the bile indicate that the differences in AUC observed are due to differences in the extent of absorption of cyclosporine. The relative bioavailability of cyclosporine. in the dogs with biliary diversion was 27% when compared to the.· control period with intact biliary system. Presence of bile results. in approximately threefold increase io the bioavai1abi1ity of cyclosporine. OUr study indicates that bile is essential for the absorption of cyclosporine. Bile has been shown to be necessary for the absorption of lipids and lipid soluble conpounds such as vitamins A, D, E, and 139 -" .. ~. --._--'- -,.,-----"----_ .... .. ----~. --.""--~-.--, .. ,,.-.... -~" VOL. 53, NO.1 JULY 1986 Research Communications in Chemical Pathology and Pharmacology K, (10) certain macromolecules such as insulin (11), heparin (12), and riboflavin (13), and sulfa drugs (14). FUrther studies to determine the effect of coadministration of bile salts on cyclosporine absorption are currently underway. If exogenous bile salts can improve cyclosporine absorption, oral cyclosporine therapy can be facilitated in liver transplant patients or in patients who malabsorb cyclosporine and the cost of cyclosporine therapy can be greatly reduced. References 1. Starzl, T.E., Klintmalm, G.B., Porter, K.A., Iwatsuki, S. and SChroter, G.P. (1981). N. Engl. J. Med. 305, 266-269. 2. caIne, R.E., Thiru, S., McMaster, P., Craddock, G.N., White, D.J.G., EVans, D.B., Dunn, D.C., Pentlow, B.D. and RoHes, K. (1978). Lancet 2, 1323-1327. 3. Griffith, B.P., Hardesty, R.L., Deeb, G.M., Starzl, T.E. and Bahnson, H.T. (1982). Ann. Surge 196, 324-329. 4. Powels, R. L., Clink, H., Cloane, J., Barrett, A.J. , Kay, H.E.M. and McElwain, T.J. (1978). Lancet 2, 1327-1331. 5. Ptachcinski, R.J., Venkataramanan, R. and Burckart, G.J. (1986). C1in. Pbarmacokin. 11, 107-132. 6. Venkataramanan, R., Burckart, G.J. and Ptachcinski, R.J. (19858). Seminars in Liver Disease 5, 357-368. 7. Andrews, W., Iwatsuki, 5., Shaw, W. and Starzl, T.E. (1985). Transplantation 39, 338. 8. Venkataramanan, R., Starzl, T.E., Yang,S., Burckart, G.J., Ptachcinski, R.J., Shaw, B.W., Iwatsuki, 5., Van Thiel, D.H., Sanghvi, A. and Se1tman H. (1985). Transplant. Proc. 17, 286-289. 9. sawchuck, R.J. and Cartier, L.L. (1981). Clin. Chern. 27, 1368-1371. 10. Forsgren, L. (1969). Acta Chirurgica scandinavica SUpplementtDII 399, 5-29. 11. nv, E., Kidron, M., Berry, E.M. and aar-on, H. (1981). Life SCiences 29, 803-809. 12. Ziv, E., E1dor, A., Kleinman, Y., Bar-on, H. and Kidron, M.~:. (1983) • Biochem. Pharmaco1. 32, 773-776. 13. Mayersohn, M., FeldlDan, S. and Gibaldi, M. (1969). J. NUtr~ 98, 288-296. 14. Nightingale, C.B., Axelson, J. and Gibald1, M. (1971) •. J •• Pharm. SCi. 60, 145-147. Copyright e 1986 By PJO Publications Ltd., Box 966, Westbury, N.Y. 11590 USA 140,-! \ J ) ~.~.~~., ' .+:.!~ .,;.'. : ........ • :i ..... ,,.. .. ";~ .. ~ ... ~-.-

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Effect of bile on cyclosporine absorption in dogs

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