title: Metabolism of tresperimus by rat aorta semicarbazide-sensitive amine oxidase (SSAO).
abstract: 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 microM, 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.
authors.affiliation: Laboratoires Founder SA., 50 route de Dijon, 21121 Dalx, France.
authors.forename: P
authors.initials: P
authors.lastname: Claud
authors.forename: Y
authors.initials: Y
authors.lastname: Artur
authors.forename: J P
authors.initials: JP
authors.lastname: Guichard
authors.forename: R
authors.initials: R
authors.lastname: Laine
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000629:Aminopropionitrile / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D002219:Carbamates / Q000378:metabolism* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003641:Deamination; D008401:Gas Chromatography-Mass Spectrometry; D006863:Hydrogen-Ion Concentration; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D008297:Male; D008861:Microsomes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002219:Carbamates; D007166:Immunosuppressive Agents; D000629:Aminopropionitrile; C092303:tresperimus; D006631:Amine Oxidase (Copper-Containing)