Pharmacokinetic profile and in vitro selective cyclooxygenase-2 inhibition by nimesulide in the dog.

The pharmacokinetic properties and in vitro potency of nimesulide, a nonsteroidal anti-inflammatory drug (NSAID) were investigated in 8 or 10 dogs after intravenous (i.v.), intramuscular (i.m.) and oral (single and multiple dose) administrations at the nominal dose of 5 mg/kg. After i.v. administration, the plasma clearance was 15.3 ± 4.2 mL/kg/h, the steady-state volume of distribution was low (0.18 ± 0.011 L/kg) and the elimination half-life 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 plasma concentration (6.1 ± 1.5 μg/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 μg/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 fifth dosage interval was 8.1 ± 2.9 μg/mL and the overall bioavailability was 58 ± 16%. The mean accumulation ratio was 1.27 ± 0.4. In vitro nimesulide 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 lipopolysaccharide (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 μM (0.49 ± 0.12 μg/mL) and 20.3 ± 2.8 μM (6.3 ± 0.86 μg/mL) giving a nimesulide COX-1/COX-2 ratio of 12.99 ± 3.41. It was concluded that at the currently recommended dosage regimen (5 mg/kg), the plasma concentration totally inhibits COX-2 and partly inhibits COX-1 isoenzyme. [ABSTRACT FROM AUTHOR]