PT  - JOURNAL ARTICLE
AU  - Li, Ying
AU  - Slatter, J. Greg
AU  - Zhang, Zhoupeng
AU  - Li, Yan
AU  - Doss, George A.
AU  - Braun, Matthew P.
AU  - Stearns, Ralph A.
AU  - Dean, Dennis C.
AU  - Baillie, Thomas A.
AU  - Tang, Wei
TI  - In Vitro Metabolic Activation of Lumiracoxib in Rat and Human Liver Preparations
AID  - 10.1124/dmd.107.019018
DP  - 2008 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 469--473
VI  - 36
IP  - 2
4099  - http://dmd.aspetjournals.org/content/36/2/469.short
4100  - http://dmd.aspetjournals.org/content/36/2/469.full
SO  - Drug Metab Dispos2008 Feb 01; 36
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