title: Comparative 1-substituted imidazole inhibition of cytochrome p450 isozyme-selective activities in human and mouse hepatic microsomes.
abstract: Inhibition of cytochrome P450(CYP)-selective reactions in a single human and a single mouse hepatic microsome preparation by fourteen 1-substituted imidazoles provides a simultaneous ranking of reaction susceptibility to a specific imidazole and the relative inhibitory potency of the imidazoles for a given reaction. CYP3A4/5 activity was inhibited (IC(50) <5 microM) by the greatest number of imidazoles, followed closely by CYP2C9. Seven imidazoles exhibited IC(50) values for CYP3A4/5 <0.3 microM (none for CYP2C9) and were exclusively above 300 MW. Nafimidone (MW, 236) exhibited an IC(50) value <0.3 microM towards CYP2D6 and CYP1A2 reactions. CYP2E1 and CYP2A6 were exclusively inhibited (IC(50) <5 microM) by imidazoles with MWs below approximately 200. In general, mouse activities exhibited lower IC(50) values than in human microsomes.
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112, USA. mfranklin@alanine.pharm.utah.edu
authors.forename: Michael R
authors.initials: MR
authors.lastname: Franklin
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Constance
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008875:Middle Aged