LC-MS/MS reveals the formation of aldehydes and iminium reactive intermediates in foretinib metabolism: phase I metabolic profiling

Abstract

Foretinib (GSK1363089) is an inhibitor of multiple receptor tyrosine kinases including MET and VEGFR, with the potential for treatment of solid tumors. In this study, we investigated the in vitro metabolic pathways for foretinib in rat liver microsomes using LC-MS/MS. Methoxylamine and potassium cyanide were used as trapping agents for aldehyde and iminium reactive intermediates, respectively, of foretinib to form a stable complex that can be identified by LC-MS/MS. Six foretinib phase I metabolites were characterized. The phase I metabolic pathways were oxidation, defluorination, reduction and hydroxylation. Additionally, four potential reactive metabolites, two aldehydes and two iminium ions, were found and the bioactivation pathways were proposed. Reporting the in vitro and reactive metabolites of foretinib is very crucial in the development stage. A literature review showed that no previous articles have provided an in vitro metabolism study of foretinib or detailed structural identification of the formed reactive metabolites.