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Vol. 30, Issue 3, 314-318, March 2002

Inhibition of Cytochromes P450 by Antifungal Imidazole Derivatives

Wenjiang Zhang, Yamini Ramamoorthy, Tansel Kilicarslan, Helma Nolte, Rachel F. Tyndale, and Edward M. Sellers

Centre for Addiction and Mental Health (R.F.T., E.M.S.), Toronto, Ontario, Canada; Departments of Pharmacology (W.Z., Y.R., T.K., H.N., R.F.T., E.M.S.), Psychiatry (E.M.S.), and Medicine (E.M.S.), University of Toronto, Ontario, Canada; and Centre for Research in Women's Health (R.F.T., E.M.S.), University of Toronto, Ontario, Canada

The interactions of a panel of antifungal agents with cytochromes P450 (P450s), as a means of predicting potential drug-drug interactions, have not yet been investigated. The objective of this study was to evaluate the specificity and selectivity of five antifungal agents using selective probe reactions for each of the eight major P450s. The index reactions used were phenacetin O-deethylation (for CYP1A2), coumarin 7-hydroxylation (CYP2A6), diclofenac 4'-hydroxylation (CYP2C9), omeprazole 5-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), 7-ethoxy-4-trifluoromethylcoumarin deethylation (CYP2B6), chlorzoxazone 6-hydroxylation (CYP2E1), and omeprazole sulfonation (CYP3A4). Five antifungal agents that include an imidazole moiety (clotrimazole, miconazole, sulconazole, tioconazole, and ketoconazole) were examined in cDNA-expressing microsomes from human lymphoblast cells or human liver microsomes. All inhibitors studied demonstrated nonselective inhibition of P450s. Ketoconazole seemed to be the most selective for CYP3A4, although it also inhibited CYP2C9. High-affinity inhibition was seen for CYP1A2 (sulconazole and tioconazole Ki, 0.4 µM), CYP2B6 (miconazole Ki, 0.05 µM; sulconazole Ki, 0.04 µM), CYP2C19 (miconazole Ki, 0.05 µM; sulconazole Ki, 0.008 µM; tioconazole Ki, 0.04 µM), CYP2C9 (sulconazole Ki, 0.01 µM), CYP2D6 (miconazole Ki, 0.70 µM; sulconazole Ki, 0.40 µM), CYP2E1 (tioconazole Ki, 0.4 µM), and CYP3A4 (clotrimazole Ki, 0.02 µM; miconazole Ki, 0.03 µM; tioconazole Ki, 0.02 µM). Therefore, this class of compounds is likely to result in significant drug-drug interactions in vivo.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics.