Data are reported as μM and were obtained from three independent
experiments. All data represent the mean ± S.D.
Reversible inhibition
behaviour of TKIs on CYP3A4 and CYP2J2
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
1/5Km–5Km range and the TKI
concentrations covered the IC50 values. The
Ki 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 Ki 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
Ki value of 1.92 μM. The
Ki 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 Ki values of
3.53 and 2.99 μM, respectively. The detailed parameters are given in
Tables 1 and 2.