Vol. 303, Issue 1, 308-313, October 2002

Sirolimus Oral Absorption in Rats Is Increased by Ketoconazole but Is Not Affected by D--Tocopheryl Poly(Ethylene Glycol 1000) Succinate

Vincent J. Wacher, Jeffrey A. Silverman¹ , Susan Wong, Paulina Tran-Tau, Amy O. Chan, Anne Chai, Xiang-Qing Yu, Daniel O'Mahony and Zeibun Ramtoola

AvMax Inc., South San Francisco, California (V.J.W., J.A.S., S.W., P.T.-T., A.O.C., A.C.) and Elan Pharmaceutical Technologies, Dublin, Ireland (X.-Q.Y., D.O.M., Z.R.)

The contributions of cytochrome P450 3A (CYP3A) and P-glycoprotein to sirolimus oral bioavailability in rats were evaluated by coadministration of sirolimus (Rapamune) with the CYP3A inhibitor ketoconazole or the P-glycoprotein inhibitor D--tocopheryl poly(ethylene glycol 1000) succinate (TPGS). Groups of six male Sprague-Dawley rats (250-300 g) were administered Rapamune (1 mg/kg) by oral gavage, alone and with ketoconazole (30 mg/kg) or TPGS (50 mg/kg). Sirolimus levels were measured in whole blood over a 6-h time course. Sirolimus C_max (6.6 ± 1.6 versus 26 ± 7 ng/ml) and area under the concentration versus time curve from 0 to 6 h (AUC_0-6) (22 ± 7 versus 105 ± 27 ng · h/ml) were increased 3- to 5-fold by ketoconazole. Median T_max (1.5-2 h) was unchanged. TPGS had no effect on sirolimus absorption. The interaction of sirolimus with P-glycoprotein was also evaluated in vitro using HCT-8 and Caco-2 cell monolayers. Consistent with published reports, sirolimus was a good inhibitor of P-glycoprotein, inhibiting polarized basolateral-to-apical flux of rhodamine 123 with an IC₅₀ of 0.625 to 1.25 µM (cyclosporine caused >80% inhibition at 5 µM). Sirolimus did not demonstrate significant polarized flux in either direction using the same monolayers (basolateral-to-apical flux was <2 times the apical-to-basolateral). Moreover, sirolimus flux was not impacted by cyclosporine, suggesting that it does not undergo P-glycoprotein-mediated transport in this system. The lack of significant sirolimus transport by P-glycoprotein may, in part, explain the lack of a TPGS effect on sirolimus absorption in rats.