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Research ArticleArticle

Involvement of Semicarbazide-Sensitive Amine Oxidase in Tresperimus Metabolism in Human and in Rat

Philippe Claud, Paul Padovani, Jean-Pierre Guichard, Yves Artur and Romuald Lainé
Drug Metabolism and Disposition May 2001, 29 (5) 735-741;
Philippe Claud
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Paul Padovani
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Jean-Pierre Guichard
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Yves Artur
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Romuald Lainé
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Abstract

The metabolism of tresperimus, a new immunosuppressive agent, was investigated in vivo and in vitro in rat and in human. Two metabolic pathways were identified at each side of the molecule with two deamination reactions on the spermidine moiety and hydrolysis of the amide bond leading to the liberation of guanidinohexylamine. As the major metabolic pathway of the drug seemed to be the oxidative deamination, the capacity of different amine oxidases to metabolize tresperimus was then tested using in vivo experiments in rat and in vitro studies in rat and human plasma. The increase of tresperimus plasma levels induced by the administration of hydralazine, an irreversible in vivo inhibitor of semicarbazide-sensitive amine oxidase (SSAO), reflected the major involvement of this enzyme in tresperimus metabolism. This result was confirmed in vitro in rat and human plasma by the use of semicarbazide, a specific SSAO inhibitor. As opposed to rat plasma, human plasma may be an interesting in vitro model to study the metabolism of a drug extensively metabolized by SSAO such as tresperimus. Indeed, SSAO activity was significantly higher in human plasma than in rat plasma. The second metabolic pathway of the drug, which only occurred in rat plasma, appeared thus as the major route of tresperimus metabolism in this biological matrix.

Footnotes

  • Send reprint requests to: Romuald Lainé, Head of Drug Metabolism, Laboratoires Fournier S.A., 50 route de Dijon, 21121 Daix, France. E-mail: r.laine{at}fournier.fr

  • Abbreviations used are::
    LC/MS
    liquid chromatography/mass spectrometry
    AUC
    area under the curve
    MAO
    monoamine oxidase
    PAO
    polyamine oxidase
    SSAO
    semicarbazide-sensitive amine oxidase
    HPLC
    high-performance liquid chromatography
    • Received July 27, 2000.
    • Accepted January 30, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (5)
Drug Metabolism and Disposition
Vol. 29, Issue 5
1 May 2001
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Research ArticleArticle

Involvement of Semicarbazide-Sensitive Amine Oxidase in Tresperimus Metabolism in Human and in Rat

Philippe Claud, Paul Padovani, Jean-Pierre Guichard, Yves Artur and Romuald Lainé
Drug Metabolism and Disposition May 1, 2001, 29 (5) 735-741;

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Research ArticleArticle

Involvement of Semicarbazide-Sensitive Amine Oxidase in Tresperimus Metabolism in Human and in Rat

Philippe Claud, Paul Padovani, Jean-Pierre Guichard, Yves Artur and Romuald Lainé
Drug Metabolism and Disposition May 1, 2001, 29 (5) 735-741;
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