RT Journal Article SR Electronic T1 In Vitro Metabolic Activation of Lumiracoxib in Rat and Human Liver Preparations JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 469 OP 473 DO 10.1124/dmd.107.019018 VO 36 IS 2 A1 Ying Li A1 J. Greg Slatter A1 Zhoupeng Zhang A1 Yan Li A1 George A. Doss A1 Matthew P. Braun A1 Ralph A. Stearns A1 Dennis C. Dean A1 Thomas A. Baillie A1 Wei Tang YR 2008 UL http://dmd.aspetjournals.org/content/36/2/469.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics