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In Vitro Metabolic Activation of Lumiracoxib in Rat and Human Liver Preparations

Ying Li, J. Greg Slatter, Zhoupeng Zhang, Yan Li, George A. Doss, Matthew P. Braun, Ralph A. Stearns, Dennis C. Dean, Thomas A. Baillie and Wei Tang
Drug Metabolism and Disposition February 2008, 36 (2) 469-473; DOI: https://doi.org/10.1124/dmd.107.019018
Ying Li
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J. Greg Slatter
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Zhoupeng Zhang
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Yan Li
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George A. Doss
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Matthew P. Braun
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Ralph A. Stearns
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Dennis C. Dean
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Thomas A. Baillie
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Wei Tang
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Abstract

Recent clinical reports have suggested that the cyclooxygenase-2 inhibitor, lumiracoxib (Prexige), may cause a rare but serious hepatotoxicity in patients. In view of the close structural resemblance between lumiracoxib and diclofenac, a widely used nonsteroidal anti-inflammatory drug whose use also has been associated with rare cases of liver injury, it is possible that the toxicity of the two agents may share a common mechanism. Because it is believed that chemically reactive metabolites may play a role as mediators of diclofenac-mediated hepatotoxicity, the present in vitro study was carried out to test the hypothesis that lumiracoxib also undergoes metabolic activation when incubated with liver microsomal preparations and hepatocytes from rats and humans. By means of liquid chromatography tandem mass spectrometry and nuclear magnetic resonance spectrometry techniques, two previously unknown N-acetylcysteine (NAC) conjugates were identified, namely, 3′-NAC-4′-hydroxy lumiracoxib (M1) and 4′-hydroxy-6′-NAC-desfluoro lumiracoxib (M2), the structures of which reveal the intermediacy of an electrophilic quinone imine species. Based on the results of studies with immunoinhibitory antibodies, it was demonstrated that the formation of M1 and M2 in human liver microsomes was catalyzed by cytochrome P450 (P450) 2C9. These findings demonstrate that lumiracoxib is subject to P450-mediated bioactivation in both rat and human liver preparations, leading to the formation of a reactive intermediate analogous to species generated during the metabolism of diclofenac.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.019018.

  • ABBREVIATIONS: P450, cytochrome P450; CID, collision-induced dissociation; LC-MS/MS, liquid chromatography tandem mass spectrometry; NAC, N-acetylcysteine; NMR, nuclear magnetic resonance spectrometry; M1,3′-NAC-4′-hydroxy lumiracoxib; M2,4′-hydroxy-6′-NAC-desfluoro lumiracoxib.

    • Received September 24, 2007.
    • Accepted November 7, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (2)
Drug Metabolism and Disposition
Vol. 36, Issue 2
1 Feb 2008
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In Vitro Metabolic Activation of Lumiracoxib in Rat and Human Liver Preparations

Ying Li, J. Greg Slatter, Zhoupeng Zhang, Yan Li, George A. Doss, Matthew P. Braun, Ralph A. Stearns, Dennis C. Dean, Thomas A. Baillie and Wei Tang
Drug Metabolism and Disposition February 1, 2008, 36 (2) 469-473; DOI: https://doi.org/10.1124/dmd.107.019018

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OtherAccelerated Communication

In Vitro Metabolic Activation of Lumiracoxib in Rat and Human Liver Preparations

Ying Li, J. Greg Slatter, Zhoupeng Zhang, Yan Li, George A. Doss, Matthew P. Braun, Ralph A. Stearns, Dennis C. Dean, Thomas A. Baillie and Wei Tang
Drug Metabolism and Disposition February 1, 2008, 36 (2) 469-473; DOI: https://doi.org/10.1124/dmd.107.019018
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