Bioactivation of Lumiracoxib by Peroxidases and Human Liver Microsomes: Identification of Multiple Quinone Imine Intermediates and GSH Adducts

Lumiracoxib (Prexige; 2-[(2-fluoro-6-chlorophenyl)amino]-5-methyl-benzeneacetic acid) is a cyclooxygenase-2 selective inhibitor for the symptomatic treatment of osteoarthritis. Recently, the drug has been withdrawn in several countries due to serious liver side effects. Li et al. recently have shown that lumiracoxib is bioactivated to a proposed quinone imine that is trapped by N-acetylcysteine (NAC) to form two NAC adducts in human and rat liver microsomal incubations. The current study demonstrated that the lumiracoxib metabolite 4′-hydroxylumiracoxib (M5) can also be bioactivated by peroxidases such as horseradish peroxidase, myeloperoxidase, and prostaglandin H synthases. Efforts were also made to identify GSH adducts formed by P450s in human liver microsomal incubations of lumiracoxib. We herein report the detection and characterization of mono-, di-, tri-, and tetra-GSH adducts in these oxidizing systems. Most of the conjugates were generated as a result of bioactivation of M5 by both peroxidases an...