Clinical pharmacokinetics of nimesulide.
Nimesulide is a selective COX-2 inhibitor used in a variety of inflammatory, pain and fever states. After healthy volunteers received oral nimesulide 100 mg in tablet, granule or suspension form the drug was rapidly and extensively absorbed. Mean peak concentrations (Cmax) of 2.86 to 6.50 mg/L were achieved within 1.22 to 2.75 hours of administration. The presence of food did not reduce either the rate or extent of nimesulide absorption. When nimesulide was administered in the suppository form, the Cmax was lower and occurred later than after oral administration; the bioavailability of nimesulide via suppository ranged from 54 to 64%, relative to that of orally administered formulations. Nimesulide is rapidly distributed and has an apparent volume of distribution ranging between 0.18 and 0.39 L/kg. It is extensively bound to albumin; the unbound fraction in plasma was 1%. The unbound fraction increased to 2 and 4% in patients with renal or hepatic insufficiency. With oral administration, the concentrations of nimesulide declined monoexponentially following Cmax. The estimated mean terminal elimination half-life varied from 1.80 to 4.73 hours. Excretion of the unchanged drug in urine and faeces is negligible. Nimesulide is largely eliminated via metabolic transformation and the principal metabolite is the 4'-hydroxy derivative (M1). Minor metabolites have been detected in urine and faeces, mainly in a conjugated form. Pharmacological tests in vivo have shown that the metabolites are endowed with anti-inflammatory and analgesic properties, although their activity is lower than that of nimesulide. Excretion in the urine and faeces accounted for 50.5 to 62.5% and 17.9 to 36.2% of an orally administered dose, respectively. The total plasma clearance of nimesulide, was 31.02 to 106.16 ml/h/kg, reflecting almost exclusive metabolic clearance. The drug has a low extraction ratio, close to 0.1. With twice daily oral or rectal administration of nimesulide, steady-state was achieved within 24 to 48 hours (2 to 4 administrations); only modest accumulation of nimesulide and M1 occurred. Gender has only a limited influence on the pharmacokinetic profiles of nimesulide and M1. The pharmacokinetic profiles of nimesulide and M1 in children and the elderly did not differ from that of healthy young individuals. Hepatic insufficiency affected the pharmacokinetics of nimesulide and M1 to a significant extent: the rate of elimination of nimesulide and M1 was remarkably reduced in comparison to the rate of elimination in healthy individuals. Therefore, a dose reduction (4 to 5 times) is required in patients with hepatic impairment. The pharmacokinetic profile of nimesulide and M1 was not altered in patients with moderate renal failure and no dose adjustment in patients with creatinine clearances higher than 1.8 L/h is envisaged. Pharmacokinetic interactions between nimesulide and other drugs given in combination [i.e. glibenclamide, cimetidine, antacids, furosemide (frusemide), theophylline, warfarin and digoxin] were absent, or of no apparent clinical relevance.
Bernareggi
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Department of Pharmacokinetics and Biochemistry, Research Centre, Monza, Italy. alberto_bernareggi@bmg.boehringer-mannheim.com
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D013449:Sulfonamides / Q000493:pharmacokinetics*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D013449:Sulfonamides; C012655:nimesulide