title: In vitro metabolic activation of lumiracoxib in rat and human liver preparations.
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.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: J Greg
authors.initials: JG
authors.lastname: Slatter
authors.forename: Zhoupeng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: George A
authors.initials: GA
authors.lastname: Doss
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Braun
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Stearns
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Dean
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Baillie
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D052246:Cyclooxygenase 2 Inhibitors / Q000378:metabolism*; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D053719:Tandem Mass Spectrometry
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D004008:Diclofenac; C473384:lumiracoxib; D000111:Acetylcysteine