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.
Highlights
Nimesulide (2-phenoxy-4-nitro-methanesulphonanilide) is a non-steroidal anti-inflammatory drug (NSAID) with preferential cyclo-oxygenase-2 inhibitory activity and which is licensed in over 50 countries worldwide for use as an anti-inflammatory, antipyretic and analgesic agent [1]
The male volunteers 30 to 55 years of age and had no clinically important abnormal physical or laboratory findings at the prescreening examination and underwent screening within 14 days of commencement of the study. They had no history of alcohol or drug abuse, positive test results of tests of HBs-Ag, HCV or HIV Ab, presence of drug allergy or existence of any surgical or medical conditions that might interfere with the pharmacokinetics of the test drug
This study gives the most comprehensive data on the metabolic transformation and recovery from the extraction pathways of nimesulide reported to date
Summary
Nimesulide (2-phenoxy-4-nitro-methanesulphonanilide) is a non-steroidal anti-inflammatory drug (NSAID) with preferential cyclo-oxygenase-2 inhibitory activity and which is licensed in over 50 countries worldwide for use as an anti-inflammatory, antipyretic and analgesic agent [1]. Nimesulide is a neutral drug (pKa 6.4; solubility in water 5.5-11.4; log POctanol/Water 2.5) is rapidly and completely absorbed from the stomach and small intestine following oral administration of the normal 100-200 mg dose [6]. It is rapidly metabolised and distributed throughout the body (volume of distribution, VZ/F 0.180.35 L/Kg) and the parent drug and metabolites are rapidly cleared principally via the kidney (CL/F 31-152 mL/h/kg) depending on dose and duration of oral drug ingestion [6]. Gender and moderate renal impairment do not markedly affect the pharmacokinetics of this drug [6,7]
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