Metabolite Profiling of Danatinib in Mice Using Ultra-High-Performance Liquid Chromatography/Tandem Mass Spectrometry In Vitro and In Vivo

Abstract

Danatinib, a brand-new compound synthesized in our laboratory for the treatment of acute myeloid leukemia (AML), demonstrates remarkable antitumor activity. However, the pharmacokinetic profile of Danatinib in mice was short with its half-life was only 0.476 h. To address this issue and optimize its therapeutic efficacy, this study investigated the metabolic profiles of Danatinib in mice, both in vitro and in vivo, using ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF MS) technology. In the in vitro study, Danatinib was analyzed using mouse liver microsomes, resulting in the identification of eight metabolites. In the in vivo study, Danatinib was administered orally to mice at 20 mg/kg; the samples of plasma, bile, feces, and urine were collected and analyzed, leading to the identification of 34 metabolites. The results showed that those metabolites were formed through various metabolic reactions including hydroxylation, carboxylation, acetylation, hydrogenation, and glucuronidation. This study provides a systematic investigation of the metabolism of Danatinib, offering valuable information for further structural modification to improve its pharmacokinetic profiles.