Sirolimus Oral Absorption in Rats Is Increased by Ketoconazole but Is Not Affected by d-α-Tocopheryl Poly(Ethylene Glycol 1000) Succinate
- Vincent J. Wacher1,
- Jeffrey A. Silverman1,1,
- Susan Wong1,
- Paulina Tran-Tau1,
- Amy O. Chan1,
- Anne Chai1,
- Xiang-Qing Yu2,
- Daniel O'Mahony2 and
- Zeibun Ramtoola2
- 1AvMax Inc., South San Francisco, California (V.J.W., J.A.S., S.W., P.T.-T., A.O.C., A.C.) and 2Elan Pharmaceutical Technologies, Dublin, Ireland (X.-Q.Y., D.O.M., Z.R.)
- Dr. Vincent J. Wacher, Director of Corporate Development, Ontogen Corporation, 6451 El Camino Real, Carlsbad, CA 92009. E-mail:vwacher{at}worldnet.att.net
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 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 >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.
Footnotes
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↵1 Current address: Sunesis Corporation, 341 Oyster Point Boulevard, South San Francisco, CA 94080.
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This work was funded by Avlan Pharmaceuticals Ltd. (Flatts, Smith, Bermuda), a joint venture of AvMax Inc. and Elan Pharmaceutical Technologies.
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DOI: 10.1124/jpet.102.036541
- Abbreviations:
- CYP3A
- cytochrome P450 3A
- P-gp
- P-glycoprotein
- MRP
- multidrug resistance-related protein
- TPGS
- d-α-tocopheryl poly(ethylene glycol 1000) succinate
- HPLC-MS
- high-pressure liquid chromatography-mass spectroscopy
- QC
- quality control
- AUC
- area under the concentration versus time curve
- P450
- cytochrome P450
- R123
- rhodamine 123
- M1–3
- unidentified sirolimus metabolites
- TBS
- Tween-phosphate-buffered saline
- 39-ODM
- 39-O-desmethylsirolimus
- CDNB
- 1-chloro-2,4-dinitrobenzene
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- Received March 25, 2002.
- Accepted June 21, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
