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Detection and Identification of Reactive Drug Metabolites Leading to Idiosyncratic Toxicity: Lapatinib as a Case Example

Rayane Mohamed, Flavia Storelli, Jonathan Sidibe, Nasim Bararpour, Jules Desmeules, Marc Ausburger, Youssef Daali and A Thomas

New pharmaceutical drug development requires more than a billion dollars and can take 12 years of research effort. New chemical entities or NCEs can be dropped from development for many reasons during this process, two major reasons being efficacy and toxicity. Lapatinib was approved in 2007 by FDA as an orally active drug against breast cancer. While some advantages were observed over chemotherapy, clinical evidences of idiosyncratic hepatoxicity were reported for this compound. Numerous studies showed that lapatinib was extensively metabolized and the formation of reactive metabolites could be the origin of the observed toxicity. It has been shown that CYP3A are the main drug metabolizing enzymes involved in the metabolism pathway of lapatinib. This study aims to identify and detect potential reactive metabolites of lapatinib formed after in vitro microsomal incubation using a comprehensive workflow for drug metabolism studies. Using micro ultra-high performance liquid chromatography coupled to high resolution mass spectrometry, we were successful to identify a new quinoneiminine reactive metabolite, which upon conjugation with gluthatione (GSH) formed a GSH related product. This product was further characterized by tandem mass spectrometry, using data-dependent and neutral loss scans. This workflow could be successfully applied to other drugs and pharmaceuticals in order to allow the comprehensive mapping of metabolism pathways and the potential identification of reactive species.