RT Journal Article
SR Electronic
T1 Inhibition of Cytochromes P450 by Antifungal Imidazole Derivatives
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 314
OP 318
DO 10.1124/dmd.30.3.314
VO 30
IS 3
A1 Wenjiang Zhang
A1 Yamini Ramamoorthy
A1 Tansel Kilicarslan
A1 Helma Nolte
A1 Rachel F. Tyndale
A1 Edward M. Sellers
YR 2002
UL http://dmd.aspetjournals.org/content/30/3/314.abstract
AB 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 phenacetinO-deethylation (for CYP1A2), coumarin 7-hydroxylation (CYP2A6), diclofenac 4′-hydroxylation (CYP2C9), omeprazole 5-hydroxylation (CYP2C19), dextromethorphanO-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 tioconazoleKi, 0.4 μM), CYP2B6 (miconazoleKi, 0.05 μM; sulconazoleKi, 0.04 μM), CYP2C19 (miconazoleKi, 0.05 μM; sulconazoleKi, 0.008 μM; tioconazoleKi, 0.04 μM), CYP2C9 (sulconazoleKi, 0.01 μM), CYP2D6 (miconazoleKi, 0.70 μM; sulconazoleKi, 0.40 μM), CYP2E1 (tioconazoleKi, 0.4 μM), and CYP3A4 (clotrimazoleKi, 0.02 μM; miconazoleKi, 0.03 μM; tioconazoleKi, 0.02 μM). Therefore, this class of compounds is likely to result in significant drug-drug interactions in vivo. The American Society for Pharmacology and Experimental Therapeutics