Pharmacokinetic profile and in vitro selective cyclooxygenase-2 inhibitionby nimesulide in the dog

The pharmacokinetic properties and in vitro potency of nimesulide, a non-st eroidal anti-inflammatory drug (NSAID) were investigated in 8 or 10 dogs af ter intravenous (i.v.), intramuscular (i.m.) and oral (single and multiple dose) administrations at the nominal dose of 5 mg/kg. After i.v. administra tion, the plasma clearance was 15.3 +/- 4.2 mL/kg/h, the steady-state volum e of distribution was low (0.18 +/- 0.011 L/kg) and the elimination half-li fe was 8.5 +/- 2.1 h. After i.m. administration, the terminal half-life was 14.0 +/- 5.3 h indicating a slow process of absorption with a maximum plas ma concentration (6.1 +/- 1.5 mug/mL) at 10.9 +/- 2.1 h postadministration and the systemic bioavailability was 69 +/- 22%. After oral administration in fasted dogs, the maximal plasma concentration (10.1 +/- 2.7 mug/mL) was observed 6.1 +/- 1.6 h after drug administration, the plasma half-life was 6.2 +/- 1.9 h and the mean bioavailability was 47 +/- 12%. After daily oral administrations for 5 days, the average plasma concentration during the fi fth dosage interval was 8.1 +/- 2.9 mug/mL and the overall bioavailability was 58 +/- 16%. The mean accumulation ratio was 1.27 +/- 0.4. In vitro nime sulide inhibitory potencies for cyclooxygenase (COX)-1 and COX-2 isoenzymes were determined using a whole blood assay. Canine clotting blood was used to test for inhibition of COX-1 activity and whole blood stimulated by lipo polysaccharide (LPS) was used to test for inhibition of COX-2 activity. The inhibitory concentration (IC50) for inhibition of COX-2 and COX-1 were 1.6 +/- 0.4 muM (0.49 +/- 0.12 mug/mL) and 20.3 +/- 2.8 muM (6.3 +/- 0.86 mug/ mL) giving a nimesulide COX-1/COX-2 ratio of 12.99 +/- 3.41. It was conclud ed that at the currently recommended dosage regimen (5 mg/kg), the plasma c oncentration totally inhibits COX-2 and partly inhibits COX-1 isoenzyme.