薬物代謝と毒性学ジャーナル
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概要

The Biotransformation and Pharmacokinetics of ¹⁴C-Nimesulide in Humans Following a Single Dose Oral Administration

David Macpherson, Stuart A Best, Layla Gedik, Alan T Hewson, Rainsford KD and Simona Parisi

Nimesulide is a preferential cyclo-oxygenase-2 inhibitory non-steroidal anti-inflammatory drug has, infrequently, been associated with hepatic reactions. To establish the extent of formation of various metabolites (some of which might be hepato-reactive) the whole body metabolism, plasma kinetics and routes of excretion of the radio-labelled drug was undertaken in 4 fasted male volunteers following an oral dose of 100 mg [14C]-nimesulide. Urine, faecal and plasma samples were collected up to 168 h post dose, the total radioactivity and plasma concentrations of nimesulide and its principle metabolite, 4-hydroxynimesulide, were determined. Radio labelled metabolites in these samples was identified by combined liquid chromatography-mass spectrometry. The mean elimination half-life of total radioactivity in the plasma and whole blood was circa 4.8 h; the ratio whole blood and plasma being circa 0.6 h. The mean elimination half-lives for nimesulide and 4-hydroxynimesulide in plasma were circa 2.5 h and circa 3.9 h, respectively. The drug was rapidly excreted and recoveries were 59-66% in the urine and 33-39% in the faeces at 168 hours. A total of 16 metabolites were identified including the conjugated metabolites, which exceeds the 5 previously identified. Nimesulide was to be metabolised by 5 pathways involving (a) cleavage of the molecule at the ether linkage (b) reduction of the NO2 group to NH2, and (c) ring hydroxylation followed by conjugation with either glucuronic acid or sulphate. In conclusion, the biotransformation pathway for nimesulide in man has now been comprehensively determined with 92% of the urinary metabolites fully characterised. The identification of some rare metabolites of nimesulide may help in understanding the mechanisms of hepatotoxicity from this drug.