title: Sirolimus oral absorption in rats is increased by ketoconazole but is not affected by D-alpha-tocopheryl poly(ethylene glycol 1000) succinate.
abstract: 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-alpha-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 IC(50) of 0.625 to 1.25 microM (cyclosporine caused >80% inhibition at 5 microM). 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.
authors.affiliation: AvMax Inc., South San Francisco, California 92009, USA. vwacher@worldnet.att.net
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Wacher
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Silverman
authors.forename: Susan
authors.initials: S
authors.lastname: Wong
authors.forename: Paulina
authors.initials: P
authors.lastname: Tran-Tau
authors.forename: Amy O
authors.initials: AO
authors.lastname: Chan
authors.forename: Anne
authors.initials: A
authors.lastname: Chai
authors.forename: Xiang-Qing
authors.initials: XQ
authors.lastname: Yu
authors.forename: Daniel
authors.initials: D
authors.lastname: O'Mahony
authors.forename: Zeibun
authors.initials: Z
authors.lastname: Ramtoola
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D007654:Ketoconazole / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014810:Vitamin E; C014225:tocophersolan; D007654:Ketoconazole; D020123:Sirolimus