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

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 [ 14 C]-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 NO 2 group to NH 2 , 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.

Targeted metabolomics of Gammarus pulex following controlled exposures to selected pharmaceuticals in water

“…Uridine, when converted to a triphosphate nucleotide (UTP), is involved in the biosynthesis of uridine diphosphate glucose (UDPG) which serves as a precursor of uridine glucuronic acid, the primary substrate for phase II glucuronidation reactions catalysed by uridine 5′-diphospho-glucuronosyltransferase (UGT). Major metabolites associated with these three pharmaceuticals are glucuronide conjugates, which support this argument ( Macpherson et al, 2013 , Walle et al, 1985 , Wu et al, 2010 ). Riboflavin also showed statistically significant 2–3 fold increases in concentration relative to control concentrations.…”

Hyaluronic acid–nimesulide conjugates as anticancer drugs against CD44-overexpressing HT-29 colorectal cancer in vitro and in vivo

“…44,45 General dosage forms of nimesulide are tablets or capsules for anti-inflammatory treatments. 46 The injectable nimesulide formulation with ethanolamine, l-cysteine, ethylenediaminetetraacetic acid (EDTA) and lactic acid, was recently developed. 47 New nimesulide formulation for intravenous injection has been scarcely reported.…”

Involvement of electron and hydrogen transfers through redox metabolism on activity and toxicity of the nimesulide

“…In addition, nimesulide can be a pro-drug of reduced form, since the reduced derivative has more antioxidant capacity and prostaglandin productions are oxidation reactions [26]. These reduced and oxidized derivatives are easily obtained in experimental conditions [27,28]. In fact, electron withdrawing groups such as methyl-sulfonamide and nitro are important for the anti-inflammatory and anti-nociceptive effects of nimesulide [3,10].…”