RT Journal Article
SR Electronic
T1 In Vitro Metabolism of Tresperimus by Human Vascular Semicarbazide-Sensitive Amine Oxidase
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 747
OP 755
DO 10.1124/dmd.30.6.747
VO 30
IS 6
A1 Philippe Claud
A1 Yves Artur
A1 Romuald Laine
YR 2002
UL http://dmd.aspetjournals.org/content/30/6/747.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics