Effects of ozagrel (OKY-046), a thromboxane synthase inhibitor, on oxidative drug-metabolizing enzymes in mouse hepatic microsomes.
The inhibitory effects of ozagrel (OZA), an imidazole derivative and a specific thromboxane synthase inhibitor, on a monooxygenase system in mouse hepatic microsomes were studied. Pentobarbital sleeping time was significantly prolonged by i.p. administration of a single dose of 100 mg/kg of OZA, and the potency of OZA for the prolongation of sleeping time was similar to that of cimetidine. In vitro, OZA inhibited aminopyrine N-demethylase, aniline hydroxylase and testosterone 6 beta- and 7 alpha-hydroxylase activities in hepatic microsomes with inhibition constants (Ki) of 0.19-3.72 mM. The potency and the mode of inhibition of OZA for these enzyme activities were similar to those of cimetidine, while no inhibitory effect of OZA on testosterone 16 alpha-hydroxylase activity was found. A spectrophotometric study revealed that the imidazole moiety of OZA binds to cytochrome P-450 and has little effect on reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase activity. These results indicated that OZA is an inhibitor of some cytochrome P-450-mediated drug metabolism in hepatic microsomes.
D000179:Acrylates / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D002927:Cimetidine / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008297:Male; D008689:Methacrylates / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010424:Pentobarbital / Q000494:pharmacology; D012890:Sleep / Q000187:drug effects; D013053:Spectrophotometry; D039181:Steroid 16-alpha-Hydroxylase; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000179:Acrylates; D008689:Methacrylates; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D039181:Steroid 16-alpha-Hydroxylase; D009251:NADPH-Ferrihemoprotein Reductase; D013930:Thromboxane-A Synthase; D010424:Pentobarbital; C034364:ozagrel