Figure Legends
Figure 1. The initial screening of imatinib, sunitinib and gefitinib inhibition with: (A) HLM, (B) CYP2J2 and (C) CYP3A4. The TKI concentrations were 1, 10 and 100 μM. Results are shown as the mean ± S.D. of at least five determinations. N.D.: not detectable.
Figure 2. Dose-response curves of TKI inhibition with (A, D) HLM, (B, E) CYP2J2 and (C, F) CYP3A4. Results are shown as the mean from at least five experiments.
Figure 3. Reversible inhibition of CYP2J2 by imatinib and gefitinib. Lineweaver–Burk plots for the inhibition of (A) imatinib and (C) gefitinib (C) on CYP2J2-mediated rivaroxaban metabolism; (B) and (D) are the corresponding Dixon plots. Data represent the mean ± S.D.
Figure 4. Reversible inhibition of CYP3A4 by imatinib, gefitinib and sunitinib. Lineweaver–Burk plots for the inhibition of (A) imatinib, (C) gefitinib and (E) sunitinib on CYP3A4-mediated rivaroxaban metabolism; (B), (D) and (F) are the corresponding Dixon plots. Data represent the mean ± S.D.
Figure 5. Effects of imatinib, sunitinib and gefitinib on rivaroxaban metabolism by (A, B and C) CYP2J2 and (D, E and F) CYP3A4 with or without a 30-min pre-incubation in the presence of NADPH. Data points are from five independent experiments.
Figure 6. (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 .
Figure 7. Molecular docking simulations of imatinib (A), sunitinib (B) and gefitinib (C) with CYP2J2, and (D, E and F) with CYP3A4.