Evidence for polymorphism in the canine metabolism of the cyclooxygenase 2 inhibitor, celecoxib.
The pharmacokinetics of celecoxib, a cyclooxygenase-2 inhibitor, was characterized in beagle dogs. Celecoxib is extensively metabolized by dogs to a hydroxymethyl 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. Hepatic microsomes from EM dogs metabolized celecoxib at a higher rate than microsomes from PM dogs. The cDNA for canine cytochrome P-450 (CYP) enzymes, CYP2B11, CYP2C21, CYP2D15, and CYP3A12 were cloned and expressed in sf 9 insect cells. Three new variants of CYP2D15 as well as a novel variant 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 metabolism in dog hepatic microsomes, providing evidence of a predominant role for the CYP2D subfamily in canine celecoxib metabolism. However, the lack of a correlation between celecoxib and bufuralol metabolism in hepatic EM or PM microsomes indicates that other CYP subfamilies besides CYP2D may contribute to the polymorphism in canine celecoxib metabolism.
Paulson
S K
SK
Department of Pharmacokinetics, Bioanalytical and Radiochemistry, G. D. Searle & Co., Skokie, Illinois, USA. Susan.K.Paulson@monsanto.com
Engel
L
L
Reitz
B
B
Bolten
S
S
Burton
E G
EG
Maziasz
T J
TJ
Yan
B
B
Schoenhard
G L
GL
D000818:Animals; D000068579:Celecoxib; D003001:Cloning, Molecular; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004285:Dogs; D004983:Ethanolamines / Q000378:metabolism; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects*; D008297:Male; D008565:Membrane Proteins; D008862:Microsomes, Liver / Q000378:metabolism; D011110:Polymorphism, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects*; D011720:Pyrazoles; D011802:Quinidine / Q000494:pharmacology; D013449:Sulfonamides / Q000378:metabolism*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004983:Ethanolamines; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; C010831:bufuralol; D003577:Cytochrome P-450 Enzyme System; C475779:cytochrome P-450 CYP3A12 (canine); D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D011802:Quinidine; D000068579:Celecoxib