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Research ArticleArticle

Potentially Reactive Cyclic Carbamate Metabolite of the Antiepileptic Drug Felbamate Produced by Human Liver Tissue In Vitro

Izet M. Kapetanovic, Cynthia D. Torchin, Charles D. Thompson, Thomas A. Miller, Patrick J. McNeilly, Timothy L. Macdonald, Harvey J. Kupferberg, James L. Perhach, R. Duane Sofia and John M. Strong
Drug Metabolism and Disposition November 1998, 26 (11) 1089-1095;
Izet M. Kapetanovic
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Cynthia D. Torchin
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Charles D. Thompson
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Thomas A. Miller
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Patrick J. McNeilly
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Timothy L. Macdonald
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Harvey J. Kupferberg
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James L. Perhach
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R. Duane Sofia
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John M. Strong
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Abstract

Felbamate (FBM) is a novel antiepileptic drug that was approved in 1993 for treatment of several forms of epilepsy. After its introduction, toxic reactions (aplastic anemia and hepatotoxicity) associated with its use were reported. It is unknown whether FBM or one of its metabolites is responsible for these idiosyncratic adverse reactions. Although the metabolism of FBM has not been fully characterized, three primary metabolites of FBM have been identified,i.e. 2-hydroxy, p-hydroxy, and monocarbamate metabolites. In addition, the monocarbamate metabolite leads to a carboxylic acid, which is the major metabolite of FBM in humans. Formation of the hydroxylated products of FBM involves cytochrome P450 enzymes, but the enzymes involved in the formation and further metabolism of the monocarbamate have not yet been elucidated. Recently, mercapturate metabolites of FBM have been identified in human urine, and a metabolic scheme involving reactive aldehyde metabolite formation from the monocarbamate metabolite has been proposed. The present study confirmed the formation of the proposed metabolites using human liver tissue in vitro. The aldehyde intermediates were trapped as oxime derivatives, and the cyclic equilibrium product (proposed as a storage and transport form for the aldehydes) was monitored directly by HPLC or GC/MS. Formation of putative toxic aldehyde intermediates and the major carboxylic acid metabolite of FBM was differentially effected with the cofactors NADP+ and NAD+. It is possible that the cofactors may influence the relative metabolism via activation and inactivation pathways.

Footnotes

  • Send reprint requests to: John M. Strong, Ph.D., MOD-1 CDER Room 2017, Food and Drug Administration, 8301 Muirkirk Road, Laurel, MD 20708. E-mail: strongj{at}cder.fda.gov

  • This work was presented in part at the 8th North American International Society for the Study of Xenobiotics Meeting (Hilton Head, SC, October 26–30, 1997).

  • Abbreviations used are::
    FBM
    felbamate
    pOH-FBM
    2-(4-hydroxyphenyl)-1,3-propanediol dicarbamate
    2OH-FBM
    2-hydroxy-2-phenyl-1,3-propanediol dicarbamate
    MCF
    2-phenyl-1,3-propanediol monocarbamate
    CPPA
    3-carbamoyl-2-phenylpropionic acid
    CBMA
    3-carbamoyl-2-phenylpropionaldehyde
    CCMF
    4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one
    ATPAL
    atropaldehyde (2-phenylpropenal)
    4MP
    4-methylpyrazole
    DDC
    diethyldithiocarbamate
    PFBH
    O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine hydrochloride
    SIM
    selected-ion monitoring
    P450
    cytochrome P450
    • Received April 7, 1998.
    • Accepted June 23, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 11
1 Nov 1998
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Research ArticleArticle

Potentially Reactive Cyclic Carbamate Metabolite of the Antiepileptic Drug Felbamate Produced by Human Liver Tissue In Vitro

Izet M. Kapetanovic, Cynthia D. Torchin, Charles D. Thompson, Thomas A. Miller, Patrick J. McNeilly, Timothy L. Macdonald, Harvey J. Kupferberg, James L. Perhach, R. Duane Sofia and John M. Strong
Drug Metabolism and Disposition November 1, 1998, 26 (11) 1089-1095;

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Research ArticleArticle

Potentially Reactive Cyclic Carbamate Metabolite of the Antiepileptic Drug Felbamate Produced by Human Liver Tissue In Vitro

Izet M. Kapetanovic, Cynthia D. Torchin, Charles D. Thompson, Thomas A. Miller, Patrick J. McNeilly, Timothy L. Macdonald, Harvey J. Kupferberg, James L. Perhach, R. Duane Sofia and John M. Strong
Drug Metabolism and Disposition November 1, 1998, 26 (11) 1089-1095;
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