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Research ArticleArticle

The Synthesis, In Vitro Reactivity, and Evidence for Formation in Humans of 5-Phenyl-1,3-oxazinane-2,4-dione, a Metabolite of Felbamate

Charles D. Thompson, Thomas A. Miller, Mary T. Barthen, Christine M. Dieckhaus, R. Duane Sofia and Timothy L. Macdonald
Drug Metabolism and Disposition April 2000, 28 (4) 434-439;
Charles D. Thompson
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Thomas A. Miller
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Mary T. Barthen
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Christine M. Dieckhaus
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R. Duane Sofia
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Timothy L. Macdonald
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Abstract

Previously we have proposed and provided evidence for a metabolic scheme leading to 3-carbamoyl-2-phenylpropionaldehyde from the antiepileptic drug felbamate. This aldehyde was found to undergo reversible cyclization to form the more stable cyclic carbamate 4-hydroxy-5-phenyl-tetrahydro-1,3-oxazin-2-one or undergo elimination to form 2-phenylpropenal. The cyclic carbamate bears structural similarity to 4-hydroxycyclophosphamide and there is an intriguing parallelism between the pathway from the cyclic carbamate to 2-phenylpropenal and the known pathway from 4-hydroxycyclophosphamide to acrolein. The similarity of these transformations led us to consider 5-phenyl-1,3-oxazinane-2,4-dione, which could arise from an oxidation of the cyclic carbamate, as a potential metabolite of felbamate. As the formation of this dione species may have both potential pharmacologic and toxicologic implications for felbamate therapy, we wished to study its reactivity. We have developed a synthesis of 5-phenyl-1,3-oxazinane-2,4-dione and evaluated its reactivity in vitro. This dione was found to undergo base-catalyzed decomposition to three products, one of which is the major human metabolite of felbamate, 3-carbamoyl-2-phenylpropionic acid. Furthermore, we have found evidence for the presence of the dione in human urine after felbamate treatment through the identification of its major in vitro decomposition product, 2-phenylacrylamide 11.

Footnotes

  • Send reprint requests to: Timothy L. Macdonald, University of Virginia, Chemistry Department, McCormick Rd., Charlottesville, VA 22901. E-mail: tlm{at}virginia.edu

  • This work was made possible by the generous financial support of Wallace Laboratories, Division of Carter-Wallace, Inc.

  • Abbreviations used are::
    LC
    liquid chromatography
    ESI
    electrospray ionization
    MS
    mass spectroscopy
    • Received April 15, 1999.
    • Accepted November 22, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (4)
Drug Metabolism and Disposition
Vol. 28, Issue 4
1 Apr 2000
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Research ArticleArticle

The Synthesis, In Vitro Reactivity, and Evidence for Formation in Humans of 5-Phenyl-1,3-oxazinane-2,4-dione, a Metabolite of Felbamate

Charles D. Thompson, Thomas A. Miller, Mary T. Barthen, Christine M. Dieckhaus, R. Duane Sofia and Timothy L. Macdonald
Drug Metabolism and Disposition April 1, 2000, 28 (4) 434-439;

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Research ArticleArticle

The Synthesis, In Vitro Reactivity, and Evidence for Formation in Humans of 5-Phenyl-1,3-oxazinane-2,4-dione, a Metabolite of Felbamate

Charles D. Thompson, Thomas A. Miller, Mary T. Barthen, Christine M. Dieckhaus, R. Duane Sofia and Timothy L. Macdonald
Drug Metabolism and Disposition April 1, 2000, 28 (4) 434-439;
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