Evidence for Polymorphism in the Canine Metabolism of the Cyclooxygenase 2 Inhibitor, Celecoxib

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Vol. 27, Issue 10, 1133-1142, October 1999

Evidence for Polymorphism in the Canine Metabolism of the Cyclooxygenase 2 Inhibitor, Celecoxib

Susan K. Paulson, Leslie Engel, Beverly Reitz, Suzanne Bolten, Earl G. Burton, Timothy J. Maziasz, Bo Yan, and Grant L. Schoenhard

Department of Pharmacokinetics, Bioanalytical and Radiochemistry (S.K.P., L.E., E.G.B., G.L.S.), Cyclooxygenase II Technology (T.J.M.), Discovery Research (B.R., S.B.), and the Statistical Department (B.Y.), G.D. Searle & Co., Skokie, Illinois

The pharmacokinetics of celecoxib, a cyclooxygenase-2 inhibitor, was characterized in beagle dogs. Celecoxib is extensivelymetabolized by dogs to a hydroxymethyl metabolite with subsequentoxidization to the carboxylic acid analog. There are at leasttwo populations of dogs, distinguished by their capacity to eliminatecelecoxib from plasma at either a fast or a slow rate after i.v.administration. Within a population of 242 animals, 45.0% wereof the EM phenotype, 53.5% were of the PM phenotype, and 1.65%could not be adequately characterized. The mean (±S.D.) plasmaelimination half-life and clearance of celecoxib were 1.72 ± 0.79h 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. Hepatic microsomes from EM dogsmetabolized celecoxib at a higher rate than microsomes from PMdogs. The cDNA for canine cytochrome P-450 (CYP) enzymes, CYP2B11,CYP2C21, CYP2D15, and CYP3A12 were cloned and expressed in sf9 insect cells. Three new variants of CYP2D15 as well as a novelvariant of CYP3A12 were identified. Canine rCYP2D15 and its variants,but not CYP2B11, CYP2C21, and CYP3A12, readily metabolized celecoxib.Quinidine (a specific CYP2D inhibitor) prevented celecoxib metabolismin dog hepatic microsomes, providing evidence of a predominantrole for the CYP2D subfamily in canine celecoxib metabolism. However,the lack of a correlation between celecoxib and bufuralol metabolismin hepatic EM or PM microsomes indicates that other CYP subfamiliesbesides CYP2D may contribute to the polymorphism in canine celecoxibmetabolism.

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