Figure 7. (A) Time- and concentration-dependent inactivation by sunitinib of CYP3A4-mediated rivaroxaban metabolism. (B) Observed inactivation rates (Kobs ) were plotted against the sunitinib concentration to calculate the inactivation kinetic constants KI and Kinact . Each point in Figure 7A was obtained from duplicate experiments.
Molecular docking simulations
Molecular docking simulations were used to elucidate the binding conformations for the interactions between the TKIs and CYP2J2 or CYP3A4. The corresponding ChemScore values of three TKIs are shown in Figure. 8. In the docking simulation between CYP2J2 and the TKIs, gefitinib had the lowest ChemScore value, followed by imatinib and then sunitinib. This ChemScore ranking was consistent with the inhibitory intensity of the TKIs on CYP2J2. Additionally, imatinib had the lowest ChemScore value in the docking simulation with CYP3A4, followed by gefitinib and then sunitinib, which was also consistent with the inhibitory intensity of these TKIs on CYP3A4.