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Research ArticleArticle

METABOLISM OF ROFECOXIB IN VITRO USING HUMAN LIVER SUBCELLULAR FRACTIONS

Donald Slaughter, Norihiro Takenaga, Ping Lu, Carol Assang, Deborah J. Walsh, Byron H. Arison, Donghui Cui, Rita A. Halpin, Leslie A. Geer, Kamlesh P. Vyas and Thomas A. Baillie
Drug Metabolism and Disposition November 2003, 31 (11) 1398-1408; DOI: https://doi.org/10.1124/dmd.31.11.1398
Donald Slaughter
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Norihiro Takenaga
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Ping Lu
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Carol Assang
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Deborah J. Walsh
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Byron H. Arison
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Donghui Cui
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Rita A. Halpin
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Leslie A. Geer
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Kamlesh P. Vyas
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Thomas A. Baillie
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Abstract

The metabolism of rofecoxib, a potent and selective inhibitor of cyclooxygenase-2, was examined in vitro using human liver subcellular fractions. The biotransformation of rofecoxib was highly dependent on the subcellular fraction and the redox system used. In liver microsomal incubations, NADPH-dependent oxidation of rofecoxib to 5-hydroxyrofecoxib predominated, whereas NADPH-dependent reduction of rofecoxib to the 3,4-dihydrohydroxy acid metabolites predominated in cytosolic incubations. In incubations with S9 fractions, metabolites resulting from both oxidative and reductive pathways were observed. In contrast to microsomes, the oxidation of rofecoxib to 5-hydroxyrofecoxib by S9 fractions followed two pathways, one NADPH-dependent and one NAD+-dependent (non-cytochrome P450), with the latter accounting for about 40% of total activity. The 5-hydroxyrofecoxib thus formed was found to undergo NADPH-dependent reduction (“back reduction”) to rofecoxib in incubations with liver cytosolic fractions. In incubations with dialyzed liver cytosol, net hydration of rofecoxib to form 3,4-dihydro-5-hydroxyrofecoxib was observed, whereas the 3,4-dihydrohydroxy acid derivatives were formed when NADPH was present. Although 3,4-dihydro-5-hydroxyrofecoxib could be reduced to the 3,4-dihydrohydroxy acid by cytosol in the presence of NADPH, the former species does not appear to serve as an intermediate in the overall reductive pathway of rofecoxib metabolism. In incubations of greater than 2 h with S9 fractions, net reductive metabolism predominated over oxidative metabolism. These in vitro results are consistent with previous findings on the metabolism of rofecoxib in vivo in human and provide a valuable insight into mechanistic aspects of the complex metabolism of this drug.

Footnotes

  • ↵† Deceased.

  • ↵1 Abbreviations used are: COX, cyclooxygenase; 5-hydroxyR, 5-hydroxyrofe-coxib; DHHA, rofecoxib-3,4-dihydrohydroxy acid; erythro-DHHA, rofecoxib-erythro-3,4-DHHA; threo-DHHA, rofecoxib-threo-3,4-DHHA; DHR, dihydrorofecoxib; DH-5-hydroxyR, 3,4-dihydro-5-hydroxyrofecoxib; TFA, trifluoroacetic acid; PDA, photodiode array; LC/MS-MS, liquid chromatography/tandem mass spectrometry; CID, collision-induced dissociation.

    • Received April 16, 2003.
    • Accepted August 18, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (11)
Drug Metabolism and Disposition
Vol. 31, Issue 11
1 Nov 2003
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Research ArticleArticle

METABOLISM OF ROFECOXIB IN VITRO USING HUMAN LIVER SUBCELLULAR FRACTIONS

Donald Slaughter, Norihiro Takenaga, Ping Lu, Carol Assang, Deborah J. Walsh, Byron H. Arison, Donghui Cui, Rita A. Halpin, Leslie A. Geer, Kamlesh P. Vyas and Thomas A. Baillie
Drug Metabolism and Disposition November 1, 2003, 31 (11) 1398-1408; DOI: https://doi.org/10.1124/dmd.31.11.1398

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Research ArticleArticle

METABOLISM OF ROFECOXIB IN VITRO USING HUMAN LIVER SUBCELLULAR FRACTIONS

Donald Slaughter, Norihiro Takenaga, Ping Lu, Carol Assang, Deborah J. Walsh, Byron H. Arison, Donghui Cui, Rita A. Halpin, Leslie A. Geer, Kamlesh P. Vyas and Thomas A. Baillie
Drug Metabolism and Disposition November 1, 2003, 31 (11) 1398-1408; DOI: https://doi.org/10.1124/dmd.31.11.1398
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