XL092 is a novel tyrosine kinase inhibitor with antitumor activity. The goal of this study was to evaluate its in vitro metabolism of XL092 using rat and human liver microsomes and hepatocytes. The metabolites were identified using ultra-high performance liquid chromatography combined with high resolution mass spectrometry. The structure of the metabolite was characterized by accurate mass, elemental composition and MS/MS spectra. The cytochrome P450 enzyme responsible for XL092 metabolism was evaluated by using recombinant human CYP450 enzymes. A total of 26 metabolites, including 21 phase I metabolites and 5 phase II metabolites, were characterized. XL092 was metabolized mainly through oxidative defluorination, hydroxylation, N-demethylation, O-demethylation, amide hydrolysis, N-dealkylation, O-dealkylation, N-oxygenation and glucuronidation. Among these metabolites, M10 (oxidative defluorination) and M17 (hydroxylation) were the most abundant metabolites. CYP3A4 and CYP2D6 were the major enzymes responsible for XL092 metabolism. Taken together, this study for the first time evaluated the in vitro metabolic profiles of XL092 in rat and human, which is of great help for us to investigate the XL092 pharmacokinetic and toxicity assessment and to predict the in vivo human metabolism.
Keywords: Metabolic pathways; Metabolite identification; Tyrosine kinase inhibitor; XL092.
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