Data are reported as μM and were obtained from three independent experiments. All data represent the mean ± S.D.

The reversible inhibition of CYP3A4 and CYP2J2 was investigated with various concentrations of rivaroxaban in the presence and absence of the TKIs (Figures 4, 5). The concentrations of rivaroxaban covered the 1/5K_m–5K_m range and the TKI concentrations covered the IC₅₀ values. The K_i value of the TKIs was fitted from the kinetic curve and the R² values and inhibition modes are shown in Tables 2 and 3. As sunitinib did not exert more than 50% inhibition even at 250 μM, the K_i value was not measured. All three TKIs showed non-competitive inhibition on CYP3A4- and CYP2J2-mediated rivaroxaban metabolism with good correlation. This was corroborated by the respective Dixon and Lineweaver–Burk plots, which also showed that the TKIs inhibited rivaroxaban in the non-competitive mode. As with the IC₅₀ results, imatinib showed the strongest inhibition on CYP3A4-mediated rivaroxaban metabolism with a K_i value of 1.92 μM. The K_i values of sunitinib and gefitinib with CYP3A4 were 13.24 and 4.91 μM, respectively, which were similar to their IC₅₀ values. Imatinib and gefitinib showed similar inhibitory effects on CYP2J2, with K_i values of 3.53 and 2.99 μM, respectively. The detailed parameters are given in Tables 1 and 2.