Inhibition of cytochromes P450 by antifungal imidazole derivatives.
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 K(i), 0.4 microM), CYP2B6 (miconazole K(i), 0.05 microM; sulconazole K(i), 0.04 microM), CYP2C19 (miconazole K(i), 0.05 microM; sulconazole K(i), 0.008 microM; tioconazole K(i), 0.04 microM), CYP2C9 (sulconazole K(i), 0.01 microM), CYP2D6 (miconazole K(i), 0.70 microM; sulconazole K(i), 0.40 microM), CYP2E1 (tioconazole K(i), 0.4 microM), and CYP3A4 (clotrimazole K(i), 0.02 microM; miconazole K(i), 0.03 microM; tioconazole K(i), 0.02 microM). Therefore, this class of compounds is likely to result in significant drug-drug interactions in vivo.
Zhang
Wenjiang
W
Department of Pharmacology, University of Toronto, Ontario, Canada.
Ramamoorthy
Yamini
Y
Kilicarslan
Tansel
T
Nolte
Helma
H
Tyndale
Rachel F
RF
Sellers
Edward M
EM
D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D007093:Imidazoles; D007527:Isoenzymes; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System