Ketoconazole: a potent inhibitor of cytochrome P-450-dependent drug metabolism in rat liver.
Ketoconazole, an orally active imidazole antimycotic agent, is shown to be a potent inhibitor of drug N-demethylase activities of liver microsomes from rats pretreated with phenobarbital or pregnenolone-16 alpha-carbonitrile, and an inhibitor of 7-ethoxyresorufin O-deethylase activity of liver microsomes from rats pretreated with 5,6-benzoflavone. Spectrophotometric studies reveal that the imidazole compound binds to the cytochrome P-450 component of the monooxygenase complex, and has little effect on NADPH-cytochrome c (P-450) reductase activity. These results are strongly suggestive that cytochrome P-450 is the site of action of this potent inhibitor of drug metabolism in liver microsomes.
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D005037:Ethylmorphine-N-Demethylase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009251:NADPH-Ferrihemoprotein Reductase / Q000037:antagonists & inhibitors; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D065607:Cytochrome P-450 Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; C019781:benzphetamine N-demethylase; D010089:Oxidoreductases, N-Demethylating; D005037:Ethylmorphine-N-Demethylase; D009251:NADPH-Ferrihemoprotein Reductase; D007654:Ketoconazole