Evidence for polymorphism in the canine metabolism of the cyclooxygenase 2inhibitor, celecoxib

The pharmacokinetics of celecoxib, a cyclooxygenase-2 inhibitor, was charac terized in beagle dogs. Celecoxib is extensively metabolized by dogs to a h ydroxymethyl metabolite with subsequent oxidization to the carboxylic acid analog. There are at least two populations of dogs, distinguished by their capacity to eliminate celecoxib from plasma at either a fast or a slow rate after i.v. administration. Within a population of 242 animals, 45.0% were of the EM phenotype, 53.5% were of the PM phenotype, and 1.65% could not be adequately characterized. The mean (+/-S.D.) plasma elimination half-life and clearance of celecoxib were 1.72 +/- 0.79 h and 18.2 +/- 6.4 ml/min/kg for EM dogs and 5.18 +/- 1.29 h and 7.15 +/- 1.41 ml/min/kg for PM dogs. He patic microsomes from EM dogs metabolized celecoxib at a higher rate than m icrosomes from PM dogs. The cDNA for canine cytochrome P-450 (CYP) enzymes, CYP2B11, CYP2C21, CYP2D15, and CYP3A12 were cloned and expressed in sf 9 i nsect cells. Three new variants of CYP2D15 as well as a novel variant of CY P3A12 were identified. Canine rCYP2D15 and its variants, but not CYP2B11, C YP2C21, and CYP3A12, readily metabolized celecoxib. Quinidine (a specific C YP2D inhibitor) prevented celecoxib metabolism in dog hepatic microsomes, p roviding evidence of a predominant role for the CYP2D subfamily in canine c elecoxib metabolism. However, the lack of a correlation between celecoxib a nd bufuralol metabolism in hepatic EM or PM microsomes indicates that other CYP subfamilies besides CYP2D may contribute to the polymorphism in canine celecoxib metabolism.