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.
|Titolo:||Metabolism of NCX 4016 : in vitro-in vivo comparison|
PICCOLI, ANGELA (Penultimo)
CARINI, MARINA (Ultimo)
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
|Data di pubblicazione:||2004|
|Digital Object Identifier (DOI):||10.1081/DMR-200027024|
|Appare nelle tipologie:||01 - Articolo su periodico|