Data di Pubblicazione:
2004
Citazione:
Metabolism of NCX 4016 : in vitro-in vivo comparison / P. Tocchetti, R. Maucci, S. Casagrande, M. Govoni, M. Orioli, A. Piccoli, M. Carini. - In: DRUG METABOLISM REVIEWS. - ISSN 0360-2532. - 36:Suppl. 1(2004), pp. 240-240. ((Intervento presentato al 15. convegno International Symposium on Microsomes and Drug Oxidations tenutosi a Mainz nel 2004 [10.1081/DMR-200027024].
Abstract:
NCX 4016 (NCX), benzoic acid, 2-(acetyloxy)-3-[nitrooxy)methyl]phenyl ester is a nitric-oxide
releasing derivative of aspirin currently under development for cardiovascular diseases. The aim of
this study was to evaluate the metabolism of the compound both in vitro (in human plasma and liver
subcellular fractions) and in vivo (in human healthy volunteers). For in vitro studies NCX was
incubated at 250 mM in human plasma, S9 and microsomes. In vivo NCX was administered to
8 male healthy subjects as a single oral dose of 1600 mg. Blood and plasma were collected at
various time points after treatment. In all samples NCX and its possible metabolites were analysed
by HPLC-UV, HPLC-MS/MS, and Gas Phase Chemiluminescence (GPC). The in vitro results
showed that NCX is rapidly and extensively metabolized to its main metabolites NCX 4015 and
salicylic acid. NCX 4015 undergoes further metabolism. In plasma this transformation seems to be
slightly slower involving firstly the formation of NCX4023, the de-acetylated metabolite and then
NCX 4015 and SA. In S9 fraction a small amount of NCX 4023 and ASA were formed. The
increase of nitrites/nitrates (NOx), the oxidative product of NO, was measured in all incubations
and strictly correlated with the decrease of the NCX 4015 metabolite. Microsomes were the most
efficient fraction in terms of NOx production. When NCX was administered to male healthy
subjects, only SA and NCX 4015 were measurable in plasma. NOx and nitrosothiols were also
measured in the systemic circulation. In conclusion, NCX is extensively and completely
metabolized both in vitro and in vivo. The metabolites found in vitro are qualitatively the same as in vivo.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
P. Tocchetti, R. Maucci, S. Casagrande, M. Govoni, M. Orioli, A. Piccoli, M. Carini
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