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Idelalisib acts as a phosphoinositide 3 kinase inhibitor, which has been approved by the US FDA for the treatment of certain hematological malignancies. The aim of this study is to profile the metabolites of idelalisib in the liver microsomes of mouse, rat, rabbit, dog, monkey and human. Idelalisib at the concentration of 20 μM was incubated with the liver microsomes in the presence of NADPH, GSH and UDPGA. The incubation samples were analyzed by ultra-high performance liquid chromatography coupled with diode array detector and linear ion trap-orbitrap tandem mass spectrometer (UHPLC-DAD-LTQ-Orbitrap-MS), and the post-acquisition data was processed by Metworks software. Under the current experimental conditions, a total of 14 metabolites were detected. The structures of the metabolites were characterized based on their accurate masses, fragmental ions and retention times. Our results suggested the following: 1) idelalisib was prone to oxidative defluorination to give rise to desfluoroidelalisib (M13). This metabolite was reactive in nature as its corresponding GSH conjugate was detected (M4). Except GSH conjugation, this metabolite can further undergo oxygenation (M7 and M14), and glucuronidation (M3); 2) oxygenation was the major metabolic pathway in liver microsomes, leading to the metabolite M10 in all test species; 3) idelalisib can be directly conjugated with glucuronide to form N+-glucuronide (M1). Species-specific metabolic difference was observed between animals and human and rat and dog have closer metabolic profiles to human compared with other animal species.UHPLC-DAD-LTQ-Orbitrap-MS method for metabolite characterization of idelalisib.14 metabolites were identified.Metabolic pathways was proposed.Species-specific metabolic difference was disclosed between animals and human.