Figure 2. 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 three determinations. N.D.: not detectable.
Determination
of IC50 values
The concentration range was determined according to the results obtained
from the initial screening. Both imatinib and gefitinib showed a strong
inhibitory effect on the rivaroxaban metabolism mediated by CYP3A4 and
CYP2J2, with IC50 values below 10 μM (Figure 3B, C and
Table 1). Additionally, sunitinib exerted a potent inhibitory effect
against CYP3A4-mediated metabolism, while the effect on CYP2J2-mediated
metabolism was not obvious with an IC50 value of 397.70
μM (Figure 3E, F). Notably, in CYP3A4-mediated rivaroxaban metabolism,
imatinib showed the strongest inhibitory activity with an
IC50 value of 4.57 μM, while gefitinib showed the
strongest inhibitory effect on metabolism by CYP2J2 with an
IC50 value of 3.71 μM. In the metabolism associated with
HLM incubation, imatinib was also the strongest inhibitor of the three
TKIs with an IC50 of 1.69 μM (Figure 3A). The detailed
IC50 values are shown in Table 1.