PMID: 9443857Mar 14, 1998Paper

Ethosuximide is primarily metabolized by CYP3A when incubated with isolated rat liver microsomes

Drug Metabolism and Disposition : the Biological Fate of Chemicals
J G SarverW A Klis

Abstract

The cytochrome P450 (CYP) subfamily responsible for ethosuximide metabolism was investigated by HPLC assay of ethosuximide incubations with isolated rat liver microsomes from control rats and from rats treated with inducing agents to enrich hepatic microsomes in selected CYP isoforms. Inducing agents included beta-naphthoflavone (BNF, CYP1A inducer), phenobarbital (PB, CYP2B/2C/3A), isoniazid (INH, CYP2E1), clotrimazole (CTZ, CYP3A), clofibrate (CLO, CYP4A), and an imidazole CTZ-analog known as CDD3543 (CYP3A). Incubations with BNF, INH, CTZ, and control microsomes showed significantly (p<0.05) more metabolite produced by CTZ microsomes vs. BNF, INH, and control microsomes at 10, 30, 60, and 120 min incubation. Ethosuximide metabolite levels generated by CTZ microsomes at 120 min were 36.5 times those of control microsomes. Correspondingly, ethosuximide concentrations were significantly (p<0.05) lower for incubations with the CTZ microsomes compared with BNF, INH, and control microsomes at 60 and 120 min. Sixty-minute incubations with all microsome groups exhibited significantly (p<0.05) higher metabolite formation rates (nmol/nmol CYP/min) for CTZ (11.8x control) and PB (9.6x control) microsomes vs. all other groups. Antibody ...Continue Reading

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