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Research ArticleArticle

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
Drug Metabolism and Disposition October 1999, 27 (10) 1133-1142;
Susan K. Paulson
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Leslie Engel
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Beverly Reitz
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Suzanne Bolten
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Earl G. Burton
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Timothy J. Maziasz
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Bo Yan
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Grant L. Schoenhard
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Abstract

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.

Footnotes

  • Send reprint requests to: Susan K. Paulson, Ph.D., G.D. Searle, 4901 Searle Parkway, Skokie, IL 60077. E-mail:Susan.K.Paulson{at}monsanto.com

  • Abbreviations used are::
    CYP
    cytochrome P-450
    PM
    poor metabolizer
    EM
    extensive metabolizer
    Cl
    clearance
    Vd
    apparent volume of distribution
    Vdss
    apparent volume of distribution at steady state
    AUC
    area under the plasma concentration-time curve
    DMSO
    dimethyl sulfoxide
    PCR
    polymerase chain reaction
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    CO
    carbon monoxide
    • Received March 29, 1999.
    • Accepted June 23, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (10)
Drug Metabolism and Disposition
Vol. 27, Issue 10
1 Oct 1999
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Research ArticleArticle

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
Drug Metabolism and Disposition October 1, 1999, 27 (10) 1133-1142;

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Research ArticleArticle

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
Drug Metabolism and Disposition October 1, 1999, 27 (10) 1133-1142;
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