Abstract
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.
Footnotes
-
This work was supported by National Institute on Drug Abuse Grant DA06889. R. F. Tyndale acknowledges the support of the Canadian Research Chair in Pharmacogenetics.
- Abbreviations used are::
- P450
- cytochrome P450
- KET
- ketoconazole
- MIC
- miconazole
- TIO
- tioconazole
- SUL
- sulconazole
- CLO
- clotrimazole
- 7-ETC
- 7-ethoxy-4-trifluoromethylcoumarin
- Received July 24, 2001.
- Accepted December 6, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|