PT - JOURNAL ARTICLE AU - Huimin Zhao AU - Siyuan Li AU - Zixin Yang AU - Ying Peng AU - Xiaohui Chen AU - Jiang Zheng TI - Identification of ketene reactive intermediate of erlotinib possibly responsible for inactivation of P450 enzymes AID - 10.1124/dmd.117.079327 DP - 2018 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.117.079327 4099 - http://dmd.aspetjournals.org/content/early/2018/01/19/dmd.117.079327.short 4100 - http://dmd.aspetjournals.org/content/early/2018/01/19/dmd.117.079327.full AB - Erlotinib (ELT), a tyrosine kinase inhibitor, is widely used for the treatment of non-small-cell lung cancer in clinic. Unfortunately, severe drug-induced liver injury and other adverse effects occurred during the treatment. Meanwhile, ELT has been reported to be a mechanism-based inactivator of CYPs 3A4 and 3A5. The objectives of this study were to identify ketene intermediate of ELT and investigate the association of the acetylenic bioactivation with the enzyme inactivation caused by ELT. A ketene intermediate was detected in human microsomal incubations of ELT, using 4-bromobenzylamine as a trapping agent. CYPs 3A4 and 3A5 mainly contributed to the bioactivation of ELT. Microsomal incubation study showed that the ketene intermediate covalently modified the enzyme protein at lysine residues and destroyed the structure of heme. The vinyl and ethyl analogs of ELT showed minor enzyme inhibitory effect (less than 20%), while ELT inactivated more than 60% of the enzyme. The present study provided a novel bioactivation pathway of ELT and facilitated the understanding of the mechanisms of ELT-induced mechanism-based enzyme inactivation and liver injury.