TY - JOUR T1 - Sirolimus Oral Absorption in Rats Is Increased by Ketoconazole but Is Not Affected by <span class="sc">d</span>-α-Tocopheryl Poly(Ethylene Glycol 1000) Succinate JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 308 LP - 313 DO - 10.1124/jpet.102.036541 VL - 303 IS - 1 AU - Vincent J. Wacher AU - Jeffrey A. Silverman AU - Susan Wong AU - Paulina Tran-Tau AU - Amy O. Chan AU - Anne Chai AU - Xiang-Qing Yu AU - Daniel O'Mahony AU - Zeibun Ramtoola Y1 - 2002/10/01 UR - http://jpet.aspetjournals.org/content/303/1/308.abstract N2 - 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 inhibitord-α-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. SirolimusCmax (6.6 ± 1.6 versus 26 ± 7 ng/ml) and area under the concentration versus time curve from 0 to 6 h (AUC0–6) (22 ± 7 versus 105 ± 27 ng · h/ml) were increased 3- to 5-fold by ketoconazole. MedianTmax (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 &gt;80% inhibition at 5 μM). Sirolimus did not demonstrate significant polarized flux in either direction using the same monolayers (basolateral-to-apical flux was &lt;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. The American Society for Pharmacology and Experimental Therapeutics ER -