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Research ArticleArticle

Pharmacokinetics and Metabolism of the Novel Anticonvulsant AgentN-(2,6-Dimethylphenyl)-5-methyl-3-isoxazolecarboxamide (D2624) in Rats and Humans

Steven W. Martin, Frances E. Bishop, Brad M. Kerr, Markus Moor, Martha Moore, Pamela Sheffels, Mohammed Rashed, J. Greg Slatter, Laurence Berthon-Cédille, Francis Lepage, Jean-Jacques Descombe, Michel Picard, Thomas A. Baillie and René H. Levy
Drug Metabolism and Disposition January 1997, 25 (1) 40-46;
Steven W. Martin
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Frances E. Bishop
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Brad M. Kerr
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Markus Moor
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Martha Moore
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Pamela Sheffels
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Mohammed Rashed
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J. Greg Slatter
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Laurence Berthon-Cédille
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Francis Lepage
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Jean-Jacques Descombe
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Michel Picard
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Thomas A. Baillie
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René H. Levy
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Abstract

N-(2,6-dimethylphenyl)-5-methyl-3-isoxazolecarboxamide (D2624) belongs to a new series of experimental anticonvulsants related to lidocaine. This study was undertaken to understand the pharmacokinetics and metabolism of D2624 in rats and humans, with emphasis on the possible formation of 2,6-dimethylaniline (2,6-DMA). After oral administration of stable isotope-labeled parent drug to rats and GC/MS analysis of plasma samples, two metabolites were identified: D3017, which is the primary alcohol, and 2,6-DMA, formed by amide bond hydrolysis of either D2624 or D3017. In urine, three metabolites of D2624 were identified: namely D3017, 2,6-DMA, and D3270 (which is the carboxylic acid derivative of D3017). Based on plasma AUC analysis, D3017 and 2,6-DMA accounted for >90% of the dose of D2624. After oral administration, D2624 was found to be well absorbed (93%), but underwent extensive first-pass metabolism in the rat, thus resulting in 5.3% bioavailability. Rat and human liver microsomal preparations were capable of metabolizing D2624 to D3017 and 2,6-DMA. The formation of D3017 was NADPH-dependent, whereas 2,6-DMA formation was NADPH-independent and probably was catalyzed by amidase(s) enzymes. In a single-dose (25–225 mg) human volunteer study, the parent drug (D2624) was not detected in plasma at any dose, whereas 2,6-DMA was detected only at the two highest doses (150 and 225 mg). D3017 was detected after all doses of parent drug, with approximate dose proportionality in AUC and a half-life of 1.3–2.2 hr. The metabolic behavior observed in humans suggests there is a marked species difference in the oxidative and hydrolytic pathways of D2624.

Footnotes

  • Send reprint requests to: Professor René H. Levy, Department of Pharmaceutics, School of Pharmacy, Box 357610, University of Washington, Seattle, WA 98195-7610.

  • This research was supported by a grant from Laboratories Biocodex, Compiègne, France, which is gratefully acknowledged.

  • Abbreviations used are::
    D2624
    N-(2,6-dimethylphenyl)-5-methyl-3isoxazolecarboxamide
    ED50
    median effective dose
    TD50
    median toxic dose
    2
    6-DMA, 2,6-dimethylaniline
    D3017
    N-(2,6-dimethylphenyl)-5-hydroxymethyl-3-isoxazolecarboxamide
    D3270
    N-(2,6-dimethylphenyl)-5-carboxy-3-isoxazolecarboxamide
    1HNMR
    proton magnetic resonance
    Fm
    fraction metabolized
    AUC
    area under the plasma concentration-time curve
    FTot
    total bioavailability
    Fabs
    absorbance bioavailability
    FLiv
    hepatic bioavailability
    BNPP
    bis(4-nitrophenyl) phosphate
    • Received March 15, 1996.
    • Accepted October 10, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 1
1 Jan 1997
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Research ArticleArticle

Pharmacokinetics and Metabolism of the Novel Anticonvulsant AgentN-(2,6-Dimethylphenyl)-5-methyl-3-isoxazolecarboxamide (D2624) in Rats and Humans

Steven W. Martin, Frances E. Bishop, Brad M. Kerr, Markus Moor, Martha Moore, Pamela Sheffels, Mohammed Rashed, J. Greg Slatter, Laurence Berthon-Cédille, Francis Lepage, Jean-Jacques Descombe, Michel Picard, Thomas A. Baillie and René H. Levy
Drug Metabolism and Disposition January 1, 1997, 25 (1) 40-46;

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Research ArticleArticle

Pharmacokinetics and Metabolism of the Novel Anticonvulsant AgentN-(2,6-Dimethylphenyl)-5-methyl-3-isoxazolecarboxamide (D2624) in Rats and Humans

Steven W. Martin, Frances E. Bishop, Brad M. Kerr, Markus Moor, Martha Moore, Pamela Sheffels, Mohammed Rashed, J. Greg Slatter, Laurence Berthon-Cédille, Francis Lepage, Jean-Jacques Descombe, Michel Picard, Thomas A. Baillie and René H. Levy
Drug Metabolism and Disposition January 1, 1997, 25 (1) 40-46;
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