Objective Nomilin and obacunone are two important limonoids that are well known for their anticancer effect. Previous studies showed that limonoids had inhibitory effect on cytochrome P450 3A4（CYP3A4）. However these...Objective Nomilin and obacunone are two important limonoids that are well known for their anticancer effect. Previous studies showed that limonoids had inhibitory effect on cytochrome P450 3A4（CYP3A4）. However these effects are inconclusive with regards to prediction of potential drug interactions. Methods Nomilin or obacunone was pre-incubated with HLMs for 30 min. Following 10-fold dilution from the pre-incubation concentration, a second incubation was performed in the presence of NADPH and cytochrome P450 substrates for 15 min. The reaction was quenched and the supernatants were analyzed by chromatography/mass spectrometry. Results In this study, nomilin and obacunone showed potent inhibitory effect on CYP3A4 with the IC_（50） values of 3.50 and 6.08 μmol/L, respectively. The inhibition of CYP3A4 was in a time-, concentration-and NADPH-dependent manner with Ki values of 2.92 and 1.25 μmol/L and Kinact values of 0.033 and 0.078 min^（-1） for nomilin and obacunone respectively. These results elucidated that they were time-dependent inhibitors for CYP3A4. Conclusion Concomitant use of limonoids and other drugs may call for extra caution for purposes of clinical safety.展开更多
基金National Natural Science Foundation of China(No.81373890 and 81430096)National Key Research and Development Program(No.2016YFE0121400)Program for Changjiang Scholars and Innovative Research Team in University(No.IRT_14R41)
文摘Objective Nomilin and obacunone are two important limonoids that are well known for their anticancer effect. Previous studies showed that limonoids had inhibitory effect on cytochrome P450 3A4（CYP3A4）. However these effects are inconclusive with regards to prediction of potential drug interactions. Methods Nomilin or obacunone was pre-incubated with HLMs for 30 min. Following 10-fold dilution from the pre-incubation concentration, a second incubation was performed in the presence of NADPH and cytochrome P450 substrates for 15 min. The reaction was quenched and the supernatants were analyzed by chromatography/mass spectrometry. Results In this study, nomilin and obacunone showed potent inhibitory effect on CYP3A4 with the IC_（50） values of 3.50 and 6.08 μmol/L, respectively. The inhibition of CYP3A4 was in a time-, concentration-and NADPH-dependent manner with Ki values of 2.92 and 1.25 μmol/L and Kinact values of 0.033 and 0.078 min^（-1） for nomilin and obacunone respectively. These results elucidated that they were time-dependent inhibitors for CYP3A4. Conclusion Concomitant use of limonoids and other drugs may call for extra caution for purposes of clinical safety.
