Data are reported as the mean ± S.D. of three incubations.
Time-dependent
inactivation of CYP3A4 by sunitinib
Given the 4.14-fold IC50 shift of sunitinib on CYP3A4
following pre-incubation with NADPH for 30 min, various concentrations
and pre-incubation times were used to determine the time-dependent
inactivation constants (Figure 7A). The maximum inactivation rate
(Kinact) and the inhibitor concentration needed
to cause half of Kinact (KI) were fitted
using the non-linear regression method. As shown in Figure 7B, the
Kinact and KI values of sunitinib were
0.0339 min–1 and 2.901 μM, respectively. The
Kinact value indicated that approximately 3.4% of
CYP3A4 was inactivated per minute when it was incubated with the
saturating concentration of sunitinib.