Inhibition of cytochromes P450 by antifungal imidazole derivatives.

Article Details

Citation

Zhang W, Ramamoorthy Y, Kilicarslan T, Nolte H, Tyndale RF, Sellers EM

Inhibition of cytochromes P450 by antifungal imidazole derivatives.

Drug Metab Dispos. 2002 Mar;30(3):314-8.

PubMed ID
11854151 [ View in PubMed
]
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 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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
ClotrimazoleCytochrome P450 2D6ProteinHumans
Unknown
Inhibitor
Details
KetoconazoleCytochrome P450 2C9ProteinHumans
Unknown
Inhibitor
Details
MiconazoleCytochrome P450 2B6ProteinHumans
Unknown
Inhibitor
Details
MiconazoleCytochrome P450 2C19ProteinHumans
Unknown
Inhibitor
Details
MiconazoleCytochrome P450 2D6ProteinHumans
Unknown
Inhibitor
Details
MiconazoleCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
MiconazoleCytochrome P450 3A4ProteinHumans
Unknown
Inhibitor
Details
SulconazoleCytochrome P450 1A2ProteinHumans
Unknown
Inhibitor
Details
SulconazoleCytochrome P450 2C9ProteinHumans
Unknown
Inhibitor
Details
TioconazoleCytochrome P450 2C19ProteinHumans
Unknown
Inhibitor
Details
TioconazoleCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
TioconazoleCytochrome P450 3A4ProteinHumans
Unknown
Inhibitor
Details