Characterization of the metabolite of cabozantinib generated from liver microsomes and hepatocytes by ultra-high performance liquid chromatography coupled to quadrupole/orbitrap high resolution mass spectrometry

• Published in: Journal of pharmaceutical and biomedical analysis 2021-10, Vol.205, p.114343-114343, Article 114343
• Main Authors: Chang, Jiawei, Chen, Hao, Chen, Jia, Sun, Xuehu, Wu, Xuesheng, Liu, Lei, Xu, Zhouwei, Chen, Weidong, Zhang, Jianlin, Wang, Xingyu, Liu, Qingwang
• Format: Article
• Language: English
• Subjects: Cabozantinib; Cytochrome P450; Hepatocytes; Liver microsomes; Metabolic pathways
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2021.114343

•In vitro metabolism of cabozantinib was investigated.•26 metabolites including 15 new metabolites were identified.•CYP 3A4 was the major enzyme responsible for cabozantinib metabolism.•Oxidative defluorination, demethylation, hydroxylation and N-oxygenation were the major metabolites. Cabozantinib is a potent inhibitor of tyrosine kinase receptor that plays key role in tumor pathogenesis. Cabozantinib has been approved by U. S. Food and Drug Administration for the treatment of cancer. The present work was aimed to explore the in vitro metabolism of cabozantinib using liver microsomes and hepatocytes from animal species and humans through ultra-high performance liquid chromatography coupled to quadrupole/orbitrap high resolution mass spectrometer. The metabolites were characterized by their elemental compositions, MS and MS/MS spectra. As a result, a total of 26 metabolites were identified, and 15 metabolites were newly reported. Among these metabolites, M12 (oxidative defluorination), M19 and M22 (demethylation), M21 (hydroxylation) and M26 (N-oxygenation) were the major metabolites in all species. Our data revealed that cabozantinib was metabolized via the following pathways: oxidative defluorination, hydroxylation, amide hydrolysis, O-dealkylation, N-oxygenation, demethylation and glucuronidation. Human recombinant cytochrome P450 (CYP) enzyme analysis revealed that metabolism of cabozantinib was mainly catalyzed by CYP3A4, while other CYP enzymes played negligible role. The current study provided valuable metabolic data of cabozantinib from different animal species and humans, which would aid in safety and efficacy assessment.