3.3 P450 enzymes responsible for M1 production and inhibition
kinetics by gefitinib.
Previous study in our laboratory showed that among the 15 kinds of P450
enzymes examined, CYP1A1, CYP1B1, CYP2C9 and CYP3A4 could catalyze the
metabolism of ningetinib into M1. According to the CLintvalues shown in Table 2, CYP1A1 played a predominant role in M1
formation, whereas CYP1B1, CYP2C9 and CYP3A4 had a minor catalytic
effect. The inhibition kinetics of gefitinib on HLMs and the four P450
enzymes was further studied. As shown in Fig. 4, gefitinib demonstrated
an inhibitive effect on M1 formation in HLMs, CYP1A1, CYP1B1 and CYP2C9
incubations. The inhibition type was determined to be a mixed-type
competitive inhibitory nature with Ki of 16.4, 0.095,
1.83 and 9.23 μM. However, the production of M1 in the CYP3A4 incubation
was not inhibited by gefitinib.