The Pharmacokinetic Profile of Nimesulide in Healthy Volunteers

Summary

After oral administration of nimesulide 100mg in tablet, granule or suspension to healthy volunteers, the drug was rapidly and extensively absorbed. Mean peak plasma concentrations of 2.86 to 4.58 mg/L were achieved within 1.22 to 3.83 hours of administration. The presence of food did not reduce either the rate or the extent of nimesulide absorption. When administered in suppository form, nimesulide peak plasma concentrations were lower and occurred later than those achieved after oral administration; the bioavailability of nimesulide given by suppository ranged from 54 to 96%, relative to that of orally administered formulations.

Nimesulide is rapidly distributed, principally throughout the extracellular fluid compartment; values for volume of distribution ranged from 0.19 to 0.39 L/kg. Nimesulide is extensively bound to plasma proteins: at concentrations ranging from 0.5 to 10 mg/L, the unbound fraction varied between 0.7 and 4.0%.

With oral administration, nimesulide concentrations decline monoexponentially following peak levels. The estimated mean terminal half-life for nimesulide varied from 1.96 to 4.73 hours.

Excretion of unchanged drug in urine and faeces is negligible. Nimesulide is mainly eliminated by metabolic transformation and the principal metabolite is the 4′-hydroxy derivative. The presence of other metabolites is being evaluated. Excretion of nimesulide metabolites in the urine and faeces accounts for about 80 and 20% of the administered dose, respectively.

Total plasma clearance of nimesulide was 39.7 to 90.9 ml/h/kg, reflecting almost exclusive metabolic clearance. The drug has a low extraction ratio, close to 0.1. Differences in gender have only a limited influence on the pharmacokinetic profile of nimesulide and its hydroxylated metabolite.

With twice-daily administration of nimesulide 100mg (tablets) or 200mg (suppositories), steady-state is achieved within 24 to 36 hours (2 to 3 administrations). With oral nimesulide 100mg twice daily, only modest accumulation of nimesulide and its 4′-hydroxy derivative occurs (R_min, 1.59 for nimesulide and 1.46 for the hydroxylated metabolite).