Characterization of genetic variation in CYP3A4 on the metabolism of cabozantinib in vitro

Cabozantinib is a multi-tyrosine kinase inhibitor and has a wide range of applications in the clinic, whose metabolism is predominately dependent on CYP3A4. This study was performed to characterize the enzymatic properties of 29 CYP3A4 alleles towards cabozantinib, and the functional changes of 5 selected alleles (the wild-type, CYP3A4.2, .8 .14 and .15) towards cabozantinib in the presence of ketoconazole. 1-100 μM cabozantinib with/without the presence of ketoconazole and CYP3A4 enzymes in the incubation system went through 30-min incubation at 37℃ and the concentrations of cabozantinib N-oxide were quantified by UPLC-MS/MS to calculate the corresponding kinetic parameters of each variant. Collectively, without the presence of ketoconazole, most variants displayed defective enzymatic activities in different degree and only CYP3A4.14 and .15 showed significantly augmented enzymatic activities. With the presence of ketoconazole, 5 tested CYP3A4 alleles, even CYP3A4.14 and .15, exhibited obvious reductions...