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Drug Metabolism & Disposition

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Rapid CommunicationShort Communication

Ethosuximide is Primarily Metabolized by CYP3A when Incubated with Isolated Rat Liver Microsomes

Jeffrey G. Sarver, Kenneth A. Bachmann, Daling Zhu and Wieslaw A. Klis
Drug Metabolism and Disposition January 1998, 26 (1) 78-82;
Jeffrey G. Sarver
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Kenneth A. Bachmann
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Daling Zhu
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Wieslaw A. Klis
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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 β-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 inhibition experiments demonstrated ethosuximide metabolite levels for PB microsomes were not affected by CYP2B1 antibodies, whereas CYP3A2 antibodies reduced metabolite levels for both PB and CTZ microsomes by over 80%. These results indicate CYP3A is primarily responsible for ethosuximide metabolism in rats.

Footnotes

  • Send reprint requests to: Jeffrey G. Sarver, Assistant Professor, Department of Pharmacology, College of Pharmacy, The University of Toledo, Toledo, OH 43606.

  • ↵2 Current address: Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226.

  • ↵3 Current address: Department of Microbiology and Immunology, Medical College of Ohio, 3000 Arlington Ave., Toledo, OH 43614.

  • Abbreviations used are::
    CYP
    cytochrome P450
    ethosuximide
    2-ethyl-2-methylsuccinimide
    BNF
    β-naphthoflavone
    PB
    phenobarbital
    CTZ
    clotrimazole
    INH
    isoniazid
    CLO
    clofibrate
    CDD3543
    1-[di-(4-fluorophenyl)phenylmethyl]imidazole
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 1
1 Jan 1998
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Rapid CommunicationShort Communication

Ethosuximide is Primarily Metabolized by CYP3A when Incubated with Isolated Rat Liver Microsomes

Jeffrey G. Sarver, Kenneth A. Bachmann, Daling Zhu and Wieslaw A. Klis
Drug Metabolism and Disposition January 1, 1998, 26 (1) 78-82;

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Rapid CommunicationShort Communication

Ethosuximide is Primarily Metabolized by CYP3A when Incubated with Isolated Rat Liver Microsomes

Jeffrey G. Sarver, Kenneth A. Bachmann, Daling Zhu and Wieslaw A. Klis
Drug Metabolism and Disposition January 1, 1998, 26 (1) 78-82;
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