Tresperimus triflutate

Tresperimus (Cellimis®), a new immunosuppressive agent, is mainly eliminated in the rat through metabolism, in which the oxidative deamination of the primary amine of the drug plays a major role. We have previously demonstrated in vivo the significant involvement of semicarbazide‐sensitive amine oxidase (SSAO) in this reaction. Rat aorta, a tissue with one of the highest specific SSAO activities, was tested as a new in vitro model to elucidate tresperimus metabolism, using a combination of liquid chromatography/mass spectrometry (LC/MS) and high‐performance liquid chromatography (HPLC) analyses. The metabolites resulting from the main metabolic pathway of the drug were formed in rat aorta homogenates. The use of various SSAO, lysyl oxidase and monoamine oxidase inhibitors confirmed that SSAO is predominantly involved in the main site of tresperimus metabolism but also in every metabolic pathway of the drug, including deamination of tresperimus metabolites M3 (desaminopropyl derivative of tresperimus) and M6 (guanidinohexylamine). A microsomal fraction of the rat aorta was used to characterize tresperimus deamination. The moderate affinity of membrane‐bound SSAO for tresperimus, with a Km value of 66 µm, was counterbalanced by a catalytic efficiency superior to that of certain physiological substrates of SSAO, such as methylamine. The rat aorta provided an interesting model with which to study tresperimus metabolism, highlighting the important role that SSAO could play as a phase I oxidative enzyme in the metabolism of certain exogenous amines at the vascular level.

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 K(m) values for the drug and K(I) 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.