alexa The Biotransformation and Pharmacokinetics of 14C-Nimesulide in Humans Following a Single Dose Oral Administration | OMICS International | Abstract
ISSN: 2157-7609

Journal of Drug Metabolism & Toxicology
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Research Article

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

David Macpherson1, Stuart A Best1, Layla Gedik1, Alan T Hewson2, Rainsford KD2* and Simona Parisi2

1Department of Metabolism Chemistry, Inveresk Research (now Charles River, Edinburgh), Tranent EH33 2NE, Scotland, UK

2Biomedical Research Centre, Sheffield Hallam University, Sheffield, S1 1WB, England, UK

*Corresponding Author:
Rainsford KD
Professor, Biomedical Research Centre
Sheffield Hallam University, Howard Street
Sheffield, S1 1WB, UK
Fax: +44-1246-583 815
E-mail: [email protected]

Received date: January 09, 2013; Accepted date: January 24, 2013; Published date: January 28, 2013

Citation: Macpherson D, Best SA, Gedik L, Hewson AT, Rainsford KD, et al. (2013) The Biotransformation and Pharmacokinetics of 14C-Nimesulide in Humans Following a Single Dose Oral Administration. J Drug Metab Toxicol 4:140. doi: 10.4172/2157-7609.1000140

Copyright: © 2013 Macpherson D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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.

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