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Research ArticleArticle

In Vitro Metabolism of Tresperimus by Human Vascular Semicarbazide-Sensitive Amine Oxidase

Philippe Claud, Yves Artur and Romuald Laine
Drug Metabolism and Disposition June 2002, 30 (6) 747-755; DOI: https://doi.org/10.1124/dmd.30.6.747
Philippe Claud
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Yves Artur
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Romuald Laine
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Abstract

Tresperimus (Cellimis), a new immunosuppressive agent is mainly eliminated through an extensive nonhepatic metabolism, in which the oxidative deamination of the primary amine of the drug takes a preponderant part. We have previously demonstrated the ability of human plasma semicarbazide-sensitive amine oxidase (SSAO) to catalyze this reaction. Therefore, the suitability of human umbilical artery, a tissue combining a high SSAO activity with monoamine oxidase activity, to study tresperimus metabolism was tested, and the kinetic behavior of tissue-bound SSAO was compared with that of plasma soluble SSAO. All the oxidized metabolites resulting from the deamination of tresperimus and of two other metabolites, desaminopropyl derivatives of tresperimus and guanidinohexylamine, were formed in vascular homogenates. Chemical inhibition experiments demonstrated the major involvement of SSAO in the metabolism of these three compounds at physiologically relevant concentrations. The microsomal fraction was used to characterize tresperimus deamination. Tissue-bound and soluble SSAO exhibited similar Km values for the drug and KI values of tresperimus toward benzylamine metabolism, a classical SSAO substrate. The kinetic behavior of both enzymes seemed to argue in favor of a same catalytic entity. Human umbilical artery constituted a relevant in vitro model to demonstrate the predominant role of SSAO in tresperimus metabolism. Our results suggest that the possible role of SSAO as Phase I oxidative enzymes has to be considered in metabolism studies for drugs encompassing primary amine.

Footnotes

  • Abbreviations used are::
    SSAO
    semicarbazide-sensitive amine oxidase
    MAO
    monoamine oxidase
    LC/MS
    liquid chromatography/mass spectrometry
    HPLC
    high-performance liquid chromatography
    BzAO
    benzylamine oxidase
    ALDH
    aldehyde dehydrogenase
    M3
    desaminopropyl derivative of tresperimus
    M6
    guanidinohexylamine
    M8
    acid derivative of M6
    LF 07-0109
    N-[4-(amino-probylamino)-butyl]-N′-(6-guanidino-hexyl)-malonamide
    • Received December 28, 2001.
    • Accepted March 11, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (6)
Drug Metabolism and Disposition
Vol. 30, Issue 6
1 Jun 2002
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Research ArticleArticle

In Vitro Metabolism of Tresperimus by Human Vascular Semicarbazide-Sensitive Amine Oxidase

Philippe Claud, Yves Artur and Romuald Laine
Drug Metabolism and Disposition June 1, 2002, 30 (6) 747-755; DOI: https://doi.org/10.1124/dmd.30.6.747

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Research ArticleArticle

In Vitro Metabolism of Tresperimus by Human Vascular Semicarbazide-Sensitive Amine Oxidase

Philippe Claud, Yves Artur and Romuald Laine
Drug Metabolism and Disposition June 1, 2002, 30 (6) 747-755; DOI: https://doi.org/10.1124/dmd.30.6.747
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