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Research ArticleArticle

Mechanistic Studies on the Reversible Metabolism of Rofecoxib to 5-Hydroxyrofecoxib in the Rat: Evidence for Transient Ring Opening of a Substituted 2-Furanone Derivative Using Stable Isotope-Labeling Techniques.

Thomas A. Baillie, Rita A. Halpin, Bogdan K. Matuszewski, Leslie A. Geer, Cynthia M. Chavez-Eng, Dennis Dean, Matthew Braun, George Doss, Allen Jones, Tina Marks, David Melillo and Kamlesh P. Vyas
Drug Metabolism and Disposition December 2001, 29 (12) 1614-1628;
Thomas A. Baillie
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Rita A. Halpin
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Bogdan K. Matuszewski
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Leslie A. Geer
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Cynthia M. Chavez-Eng
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Dennis Dean
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Matthew Braun
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George Doss
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Allen Jones
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Tina Marks
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David Melillo
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Kamlesh P. Vyas
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Abstract

Rofecoxib is a potent and highly selective cyclooxygenase-2 inhibitor used for the treatment of osteoarthritis and pain. Following administration of [4-14C]rofecoxib to intact rats, the plasma Cmax (at ∼1 h) was followed by a secondary Cmax (at ∼10 h), which was not observed in bile duct-cannulated rats. Following administration of [4-14C]5-hydroxyrofecoxib to intact or bile duct-cannulated rats, radiolabeled rofecoxib was detected in plasma, and once again a secondary Cmax for rofecoxib was observed (at ∼10 h), which occurred only in the intact animals. These results indicate that reversible metabolism of rofecoxib to 5-hydroxyrofecoxib occurs in the rat and that the process is dependent upon an uninterrupted bile flow. Studies on the contents of the gastrointestinal tract of rats showed that conversion of 5-hydroxyrofecoxib to parent compound occurs largely in the lower intestine. Treatment of rats with [5-18O]5-hydroxyrofecoxib, followed by liquid chromatography-tandem mass spectrometry analyses of plasma samples, confirmed that 5-hydroxyrofecoxib undergoes metabolism to the parent drug, yielding [1-18O]rofecoxib, [2-18O]rofecoxib, and unlabeled rofecoxib. Similarly, treatment with [1,2-18O2]rofecoxib afforded the same three isotopic variants of rofecoxib. These findings are consistent with a metabolic sequence involving 5-hydroxylation of rofecoxib, biliary elimination of the corresponding glucuronide, and deconjugation of the glucuronide in the lower gastrointestinal tract. Reduction of the 5-hydroxyrofecoxib thus liberated yields a hydroxyacid that cyclizes spontaneously to regenerate rofecoxib, which is reabsorbed and enters the systemic circulation. This sequence represents a novel form of enterohepatic recycling and reflects the susceptibility of 5-hydroxyrofecoxib, as well as rofecoxib itself, to reversible 2-furanone ring opening under in vivo conditions.

Footnotes

  • Abbreviations used are::
    COX
    cyclooxygenase
    GI
    gastrointestinal tract
    DMSO
    dimethyl sulfoxide
    PEG-400
    polyethylene glycol-400
    TFA
    trifluoroacetic acid
    HPLC
    high-performance liquid chromatography
    MS
    mass spectrometry
    DMF
    dimethylformamide
    AUC
    area under the plasma concentration versus time curve
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    • Received June 5, 2001.
    • Accepted August 15, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (12)
Drug Metabolism and Disposition
Vol. 29, Issue 12
1 Dec 2001
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Research ArticleArticle

Mechanistic Studies on the Reversible Metabolism of Rofecoxib to 5-Hydroxyrofecoxib in the Rat: Evidence for Transient Ring Opening of a Substituted 2-Furanone Derivative Using Stable Isotope-Labeling Techniques.

Thomas A. Baillie, Rita A. Halpin, Bogdan K. Matuszewski, Leslie A. Geer, Cynthia M. Chavez-Eng, Dennis Dean, Matthew Braun, George Doss, Allen Jones, Tina Marks, David Melillo and Kamlesh P. Vyas
Drug Metabolism and Disposition December 1, 2001, 29 (12) 1614-1628;

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Research ArticleArticle

Mechanistic Studies on the Reversible Metabolism of Rofecoxib to 5-Hydroxyrofecoxib in the Rat: Evidence for Transient Ring Opening of a Substituted 2-Furanone Derivative Using Stable Isotope-Labeling Techniques.

Thomas A. Baillie, Rita A. Halpin, Bogdan K. Matuszewski, Leslie A. Geer, Cynthia M. Chavez-Eng, Dennis Dean, Matthew Braun, George Doss, Allen Jones, Tina Marks, David Melillo and Kamlesh P. Vyas
Drug Metabolism and Disposition December 1, 2001, 29 (12) 1614-1628;
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