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Research ArticleArticle

The Absorption, Distribution, Metabolism and Excretion of Rofecoxib, a Potent and Selective Cyclooxygenase-2 Inhibitor, in Rats and Dogs

Rita A. Halpin, Leslie A. Geer, Kanyin E. Zhang, Tina M. Marks, Dennis C. Dean, Allen N. Jones, David Melillo, George Doss and Kamlesh P. Vyas
Drug Metabolism and Disposition October 2000, 28 (10) 1244-1254;
Rita A. Halpin
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Leslie A. Geer
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Kanyin E. Zhang
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Tina M. Marks
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Dennis C. Dean
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Allen N. Jones
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David Melillo
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George Doss
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Kamlesh P. Vyas
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Abstract

Absorption, distribution, metabolism, and excretion studies were conducted in rats and dogs with rofecoxib (VIOXX, MK-0966), a potent and highly selective inhibitor of cyclooxygenase-2 (COX-2). In rats, the nonexponential decay during the terminal phase (4- to 10-h time interval) of rofecoxib plasma concentration versus time curves after i.v. or oral administration of [14C]rofecoxib precluded accurate determinations of half-life, AUC0–∞(area under the plasma concentration versus time curve extrapolated to infinity), and hence, bioavailability. After i.v. administration of [14C]rofecoxib to dogs, plasma clearance, volume of distribution at steady state, and elimination half-life values of rofecoxib were 3.6 ml/min/kg, 1.0 l/kg, and 2.6 h, respectively. Oral absorption (5 mg/kg) was rapid in both species with Cmax occurring by 0.5 h (rats) and 1.5 h (dogs). Bioavailability in dogs was 26%. Systemic exposure increased with increasing dosage in rats and dogs after i.v. (1, 2, and 4 mg/kg), or oral (2, 5, and 10 mg/kg) administration, except in rats where no additional increase was observed between the 5 and 10 mg/kg doses. Radioactivity distributed rapidly to tissues, with the highest concentrations of the i.v. dose observed in most tissues by 5 min and by 30 min in liver, skin, fat, prostate, and bladder. Excretion occurred primarily by the biliary route in rats and dogs, except after i.v. administration of [14C]rofecoxib to dogs, where excretion was divided between biliary and renal routes. Metabolism of rofecoxib was extensive. 5-Hydroxyrofecoxib-O-β-d-glucuronide was the major metabolite excreted by rats in urine and bile. 5-Hydroxyrofecoxib, rofecoxib-3′,4′-dihydrodiol, and 4′-hydroxyrofecoxib sulfate were less abundant, whereascis- and trans-3,4-dihydro-rofecoxib were minor. Major metabolites in dog were 5-hydroxyrofecoxib-O-β-d-glucuronide (urine), trans-3,4-dihydro-rofecoxib (urine), and 5-hydroxyrofecoxib (bile).

Footnotes

  • Send reprint requests to: Kamlesh P. Vyas, Ph.D., Merck Research Laboratories, Merck & Co., Inc., WP75A-203, West Point, PA 19486. E-mail: kamlesh_vyas{at}merck.com

  • ↵1 Current address: Agouron Pharmaceuticals, Inc., 4215 Sorrento Valley Blvd., San Diego CA, 92121.

  • ↵4 R. Zamboni, unpublished data, Merck Frosst Canada, Kirkland, Quebec.

  • ↵5 T. A. Baillie and coworkers, manuscript in preparation, Merck Research Laboratories, West Point, PA.

  • ↵3 VIOXX is a registered trademark of Merck & Co., Inc.

  • Abbreviations used are::
    PG
    prostaglandin
    COX
    cyclooxygenase
    PGHS
    prostaglandin endoperoxide synthase
    TFA
    trifluoroacetic acid
    DMSO
    dimethyl sulfoxide
    • Received March 16, 2000.
    • Accepted July 20, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (10)
Drug Metabolism and Disposition
Vol. 28, Issue 10
1 Oct 2000
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Research ArticleArticle

The Absorption, Distribution, Metabolism and Excretion of Rofecoxib, a Potent and Selective Cyclooxygenase-2 Inhibitor, in Rats and Dogs

Rita A. Halpin, Leslie A. Geer, Kanyin E. Zhang, Tina M. Marks, Dennis C. Dean, Allen N. Jones, David Melillo, George Doss and Kamlesh P. Vyas
Drug Metabolism and Disposition October 1, 2000, 28 (10) 1244-1254;

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Research ArticleArticle

The Absorption, Distribution, Metabolism and Excretion of Rofecoxib, a Potent and Selective Cyclooxygenase-2 Inhibitor, in Rats and Dogs

Rita A. Halpin, Leslie A. Geer, Kanyin E. Zhang, Tina M. Marks, Dennis C. Dean, Allen N. Jones, David Melillo, George Doss and Kamlesh P. Vyas
Drug Metabolism and Disposition October 1, 2000, 28 (10) 1244-1254;
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