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Vol. 31, Issue 4, 439-446, April 2003

Comparative Effects of Thiazolidinediones on in Vitro P450 Enzyme Induction and Inhibition

Jasminder Sahi, Christopher B. Black, Geraldine A. Hamilton, Xianxian Zheng, Summer Jolley, Kelly A. Rose, Darryl Gilbert, Edward L. LeCluyse, and Michael W. Sinz1

Department of Pharmacokinetics Pharmacodynamics and Metabolism (J.S., K.A.R., M.W.S.) and Molecular Biology (X.Z.), Pfizer Global Research and Development, Ann Arbor, Michigan; Cedra Corporation, Austin, Texas (C.B.B.) and University of North Carolina at Chapel Hill, School of Pharmacy, Chapel Hill, North Carolina (G.A.H., S.J., D.G., E.L.L.)

Rosiglitazone and pioglitazone are thiazolidinediones used for treatment of noninsulin-dependent diabetes mellitus. These compounds, along with troglitazone, were evaluated for the ability to induce cytochrome P450 enzymes (P450) in primary human hepatocyte cultures and to inhibit P450 in human microsomes. In induction studies, all three thiazolidinediones caused a dose-dependent increase in CYP3A4 activity and immunoreactive protein. While troglitazone was the most potent, rosiglitazone and pioglitazone generally exceeded troglitazone in absolute CYP3A4 activity achieved at concentrations >= 10 µM. A comparable concentration-dependent increase in CYP2B6 immunoreactive protein was observed with all three thiazolidinediones. Microarray analysis revealed rifampin > troglitazone > pioglitazone > rosiglitazone in terms of CYP3A4 mRNA induction potential with 10 µM compound. Inhibition studies conducted for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2A6, and CYP2E1 showed troglitazone to be the most nonselective and potent inhibitor followed by rosiglitazone and pioglitazone. In vitro, the thiazolidinediones were strong inhibitors of CYP2C8, with Ki values between 1.7 and 5.6 µM, and of CYP3A4, with Ki values between 1.6 and 11.8 µM. Troglitazone, in addition, inhibited CYP2C9 (Ki 0.6 µM). Although the inhibitory effects of the thiazolidinediones have not been demonstrated clinically, our results suggest there is potential for interactions with CYP2C8 substrates. This is the first report of in vitro induction of P450 enzymes by rosiglitazone and pioglitazone. While only the induction of CYP3A4 by troglitazone has been demonstrated in vivo, these results suggest that other thiazolidinediones may have the potential to cause clinically significant drug interactions at sufficiently high doses.

1 M. W. Sinz is presently at Bristol-Myers Squibb, Wallingford, CT 06422.

Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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