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Research ArticleArticle

Characterization of Carbamazepine Metabolism in a Mouse Model of Carbamazepine Teratogenicity

Benny M. Amore, Thomas F. Kalhorn, Gary L. Skiles, Ann P. Hunter, Greg D. Bennett, Richard H. Finnell, Sidney D. Nelson and John T. Slattery
Drug Metabolism and Disposition August 1997, 25 (8) 953-962;
Benny M. Amore
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Thomas F. Kalhorn
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Gary L. Skiles
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Ann P. Hunter
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Greg D. Bennett
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Richard H. Finnell
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Sidney D. Nelson
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John T. Slattery
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Abstract

The disposition of carbamazepine (CBZ) was investigated in the SWV mouse. A 14C-CBZ dose was administered to CBZ pretreated mice, and the distribution of radiolabeled material was determined. Twenty-four hours after the 14C-CBZ dose, 92.5% of the dose was accounted for in urine (56%), in the visera and carcass (22%), in feces (11%), and expired as 14CO2(2%). CBZ metabolites present in hydrolyzed urine were also identified using a combination of spectroscopic techniques. CBZ, CBZ-10,11-epoxide (CBZE), 2- and 3-hydroxy-CBZ, methylsulfonyl-CBZ, and glucuronides of CBZ and CBZE accounted for 64% of total urinary radioactivity (0–24 hr) in CBZ pretreated mice. Minor metabolites of CBZ included novel cysteine and N-acetylcysteine conjugates of CBZ, as well as a methylsulfonyl conjugate of CBZE not previously reported. The urinary excretion of these thioether conjugates was increased in CBZ/phenobarbital pretreated mice and decreased in CBZ/stiripentol pretreated mice in comparison with CBZ-only treated mice. Preliminary studies of the effects of phenobarbital and stiripentol on the urinary abundance of these metabolites are consistent with the modulation of teratogenicity in the SWV mouse by the same pretreatments. These data suggest the formation of thioether metabolites of CBZ may be related to CBZ teratogenicity in the SWV mouse.

Footnotes

  • Send reprint requests to: Dr. John T. Slattery, Department of Pharmaceutics, Box 357610, University of Washington, Seattle, WA 98195-7610.

  • This research was supported in part by the National Institutes of Health Grant NS 28192.

  • Abbreviations used are::
    CBZ
    carbamazepine
    PB
    phenobarbital
    CBZE
    carbamazepine-10,11-epoxide
    STP
    stiripentol
    LSC
    liquid scintillation counting
    ip
    intraperitoneal
    BaOH
    barium hydroxide
    LC/MS/MS
    liquid chromatography tandem mass spectrometry
    ESI
    electrospray ionization
    CID
    collision-induced dissociation
    NAC
    N-acetylcysteine
    CYS
    cysteine
    EI
    electron ionization
    GSH
    glutathione
    • Received November 27, 1996.
    • Accepted April 15, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 8
1 Aug 1997
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Research ArticleArticle

Characterization of Carbamazepine Metabolism in a Mouse Model of Carbamazepine Teratogenicity

Benny M. Amore, Thomas F. Kalhorn, Gary L. Skiles, Ann P. Hunter, Greg D. Bennett, Richard H. Finnell, Sidney D. Nelson and John T. Slattery
Drug Metabolism and Disposition August 1, 1997, 25 (8) 953-962;

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Research ArticleArticle

Characterization of Carbamazepine Metabolism in a Mouse Model of Carbamazepine Teratogenicity

Benny M. Amore, Thomas F. Kalhorn, Gary L. Skiles, Ann P. Hunter, Greg D. Bennett, Richard H. Finnell, Sidney D. Nelson and John T. Slattery
Drug Metabolism and Disposition August 1, 1997, 25 (8) 953-962;
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