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Research ArticleArticle

The Disposition and Metabolism of Rofecoxib, a Potent and Selective Cyclooxygenase-2 Inhibitor, in Human Subjects

Rita A. Halpin, Arturo G. Porras, Leslie A. Geer, Margaret R. Davis, Donghui Cui, George A. Doss, Eric Woolf, Donald Musson, Catherine Matthews, Ralph Mazenko, Jules I. Schwartz, Kenneth C. Lasseter, Kamlesh P. Vyas and Thomas A. Baillie
Drug Metabolism and Disposition June 2002, 30 (6) 684-693; DOI: https://doi.org/10.1124/dmd.30.6.684
Rita A. Halpin
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Arturo G. Porras
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Leslie A. Geer
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Margaret R. Davis
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Donghui Cui
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George A. Doss
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Eric Woolf
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Donald Musson
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Catherine Matthews
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Ralph Mazenko
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Jules I. Schwartz
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Kenneth C. Lasseter
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Kamlesh P. Vyas
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Thomas A. Baillie
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Abstract

The disposition and metabolism of rofecoxib, a selective cyclooxygenase-2 inhibitor, were examined in healthy human subjects and in cholecystectomy patients. After oral administration of [14C]rofecoxib (125 mg, 100 μCi) to healthy subjects, the mean concentrations of total radioactivity and rofecoxib in plasma as a function of time indicated that thetmax was achieved at 9 h postdose. After tmax, levels of both radioactivity and rofecoxib decreased in a parallel, exponential fashion (effectivet1/2 ≈ 17 h). A similar result was obtained after oral administration of [14C]rofecoxib (142 mg, 100 μCi) to cholecystectomy patients equipped with an L-tube. In healthy subjects, radioactivity was recovered predominantly from the urine (71.5% of dose), with a small amount excreted in feces (14.2%). In patients with an L-tube, half the radioactive dose was recovered in feces, with a lesser amount excreted in urine (28.8%) and a negligible fraction in bile (1.8%). Rofecoxib underwent extensive metabolism in humans, and very little parent drug was recovered unchanged in urine (<1%). Products resulting from both oxidative and reductive pathways were identified by a combination of 1H NMR and liquid chromatography-tandem mass spectrometry analyses, and included rofecoxib-3′,4′-trans-dihydrodiol, 4′-hydroxyrofecoxib-O-β-d-glucuronide, diastereomeric 5-hydroxyrofecoxib-O-β-d-glucuronide conjugates, 5-hydroxyrofecoxib, rofecoxib-erythro-3,4-dihydrohydroxy acid, and rofecoxib-threo-3,4-dihydrohydroxy acid. Interconversion of rofecoxib and 5-hydroxyrofecoxib appeared not to be a quantitatively important pathway of rofecoxib disposition in human subjects, in contrast to previous findings in rats.

Footnotes

  • ↵1 Present address: Wyeth-Ayerst Pharmaceuticals, 500 Arcola Road, S3414, Collegeville, PA 19426-3930.

  • Abbreviations used are::
    COX-2
    cyclooxygenase-2
    AUC
    area under the plasma concentrations versus time curve
    Cmax
    maximum plasma concentration
    CH3CN
    acetonitrile
    DHHA
    dihydrohydroxy acid
    DMSO-d6
    deuterated dimethyl sulfoxide
    DPS
    disintegrations per second
    HPLC
    high performance liquid chromatography
    ICG
    indocyanine green
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    MeOH
    methanol
    NSAID
    nonsteroidal anti-inflammatory drug
    p.o.
    peroral
    TFA
    trifluoroacetic acid
    tmax
    time of maximum plasma concentration
    • Received September 14, 2001.
    • Accepted February 13, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (6)
Drug Metabolism and Disposition
Vol. 30, Issue 6
1 Jun 2002
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Research ArticleArticle

The Disposition and Metabolism of Rofecoxib, a Potent and Selective Cyclooxygenase-2 Inhibitor, in Human Subjects

Rita A. Halpin, Arturo G. Porras, Leslie A. Geer, Margaret R. Davis, Donghui Cui, George A. Doss, Eric Woolf, Donald Musson, Catherine Matthews, Ralph Mazenko, Jules I. Schwartz, Kenneth C. Lasseter, Kamlesh P. Vyas and Thomas A. Baillie
Drug Metabolism and Disposition June 1, 2002, 30 (6) 684-693; DOI: https://doi.org/10.1124/dmd.30.6.684

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Research ArticleArticle

The Disposition and Metabolism of Rofecoxib, a Potent and Selective Cyclooxygenase-2 Inhibitor, in Human Subjects

Rita A. Halpin, Arturo G. Porras, Leslie A. Geer, Margaret R. Davis, Donghui Cui, George A. Doss, Eric Woolf, Donald Musson, Catherine Matthews, Ralph Mazenko, Jules I. Schwartz, Kenneth C. Lasseter, Kamlesh P. Vyas and Thomas A. Baillie
Drug Metabolism and Disposition June 1, 2002, 30 (6) 684-693; DOI: https://doi.org/10.1124/dmd.30.6.684
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