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Research ArticleArticle

Pharmacokinetics, Tissue Distribution, Metabolism, and Excretion of Celecoxib in Rats

Susan K. Paulson, Ji Y. Zhang, Alan P. Breau, Jeremy D. Hribar, Norman W. K. Liu, Susan M. Jessen, Yvette M. Lawal, J. Nita Cogburn, Christopher J. Gresk, Charles S. Markos, Timothy J. Maziasz, Grant L. Schoenhard and Earl G. Burton
Drug Metabolism and Disposition May 2000, 28 (5) 514-521;
Susan K. Paulson
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Ji Y. Zhang
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Alan P. Breau
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Jeremy D. Hribar
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Norman W. K. Liu
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Susan M. Jessen
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Yvette M. Lawal
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J. Nita Cogburn
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Christopher J. Gresk
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Charles S. Markos
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Timothy J. Maziasz
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Grant L. Schoenhard
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Earl G. Burton
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Abstract

The pharmacokinetics, tissue distribution, metabolism, and excretion of celecoxib, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide, a cyclooxygenase-2 inhibitor, were investigated in rats. Celecoxib was metabolized extensively after i.v. administration of [14C]celecoxib, and elimination of unchanged compound was minor (less than 2%) in male and female rats. The only metabolism of celecoxib observed in rats was via a single oxidative pathway. The methyl group of celecoxib is first oxidized to a hydroxymethyl metabolite, followed by additional oxidation of the hydroxymethyl group to a carboxylic acid metabolite. Glucuronide conjugates of both the hydroxymethyl and carboxylic acid metabolites are formed. Total mean percent recovery of the radioactive dose was about 100% for both the male rat (9.6% in urine; 91.7% in feces) and the female rat (10.6% in urine; 91.3% in feces). After oral administration of [14C]celecoxib at doses of 20, 80, and 400 mg/kg, the majority of the radioactivity was excreted in the feces (88–94%) with the remainder of the dose excreted in the urine (7–10%). Both unchanged drug and the carboxylic acid metabolite of celecoxib were the major radioactive components excreted with the amount of celecoxib excreted in the feces increasing with dose. When administered orally, celecoxib was well distributed to the tissues examined with the highest concentrations of radioactivity found in the gastrointestinal tract. Maximal concentration of radioactivity was reached in most all tissues between 1 and 3 h postdose with the half-life paralleling that of plasma, with the exception of the gastrointestinal tract tissues.

Footnotes

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

  • ↵1 Current address: Genentech Inc., South San Francisco, CA.

  • Abbreviations used are::
    PG
    prostaglandins
    COX
    cyclooxygenase
    LSC
    liquid scintillation counting
    MS
    mass spectrometry
    SPE
    solid-phase extraction
    CID
    collision-induced dissociation
    AUC
    area under the plasma concentration-time curve
    Vd
    volume of distribution
    Cmax
    maximum plasma concentration
    NSAIDs
    nonsteroidal anti-inflammatory drugs
    GI
    gastrointestinal
    PEG
    polyethylene glycol
    • Received September 27, 1999.
    • Accepted January 10, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (5)
Drug Metabolism and Disposition
Vol. 28, Issue 5
1 May 2000
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Research ArticleArticle

Pharmacokinetics, Tissue Distribution, Metabolism, and Excretion of Celecoxib in Rats

Susan K. Paulson, Ji Y. Zhang, Alan P. Breau, Jeremy D. Hribar, Norman W. K. Liu, Susan M. Jessen, Yvette M. Lawal, J. Nita Cogburn, Christopher J. Gresk, Charles S. Markos, Timothy J. Maziasz, Grant L. Schoenhard and Earl G. Burton
Drug Metabolism and Disposition May 1, 2000, 28 (5) 514-521;

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Research ArticleArticle

Pharmacokinetics, Tissue Distribution, Metabolism, and Excretion of Celecoxib in Rats

Susan K. Paulson, Ji Y. Zhang, Alan P. Breau, Jeremy D. Hribar, Norman W. K. Liu, Susan M. Jessen, Yvette M. Lawal, J. Nita Cogburn, Christopher J. Gresk, Charles S. Markos, Timothy J. Maziasz, Grant L. Schoenhard and Earl G. Burton
Drug Metabolism and Disposition May 1, 2000, 28 (5) 514-521;
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