目的 基于细胞色素P450(CYP450)代谢酶探究补骨脂素和异补骨脂素对黄独乙素在大鼠体内代谢的影响。方法 采用大鼠离体循环肝灌流方法,考察大鼠分别给予补骨脂素或异补骨脂素1、3、7 d后,黄独乙素在肝脏中的代谢情况;利用UPLC-MS/MS检测循环灌流液中剩余黄独乙素的含量;通过大鼠眼内眦取血的方法研究大鼠分别给予补骨脂素或异补骨脂素干预1周,再给予黄药子提取物(10 g·kg^-1)后体内黄独乙素的药动学变化,药动学参数采用DAS 2.0软件中的非房室模型法进行计算。结果 大鼠给予补骨脂素或异补骨脂素后,循环灌流液中黄独乙素的含量相对增加,且补骨脂素或异补骨脂素给药时间延长后,对酶的抑制程度更强;当大鼠给予补骨脂素或异补骨脂素干预后,与非干预组(黄药子提取物组)相比,药时曲线下面积(AUC_0~t)和平均驻留时间(MRT_0~t)增加,消除半衰期(t_1/2Z)减小。结论 补骨脂素/异补骨脂素可通过抑制肝脏中CYP450酶的活性降低其对黄独乙素的代谢,使黄独乙素在肝脏中代谢减少,造成蓄积,临床用药应注意含有补骨脂素/异补骨脂素或黄独乙素中药在合用时可能产生的药物相互作用。

Objective To investigate the effect of psoralen and isopsoralen on the metabolism of diosbulbin B in rats based on cytochrome P450 enzyme system (CYP450). Methods After administration of psoralen or isopsoralen for 1, 3, 7 days, respectively, isolated circulatory liver perfusion was used to study the metabolism of diosbulbin B in the liver of rats. UPLC-MS /MS was used to detect the content of diosbulbin B in circulating perfusate. When rats were treated with psoralen/isopsoralen for one week before administration of extraction of Dioscorea bulbifera L. (10 g·kg^-1), blood was taken from the inner canthus of rats and the pharmacokinetic parameters of diosbulbin B were calculated by non-compartment model in DAS 2.0 software. Results After orally administration of psoralen/isopsoralen for different days, the amount of diosbulbin B in circulating perfusate was relatively increased, and psoralen/isopsoralen showed stronger inhibition to the enzyme after prolonged administration. Compared with the non-intervention group, after treating with psoralen/isopsoralen, the values of area under the curve (AUC_0～t) and mean residence time (MRT_0～t) were increased and the elimination half life (t_1/2Z) values was decreased. Conclusion Psoralen/isopsoralen can inhibit the activity of CYP450 enzyme in the liver, reduce its metabolism of diosbulbin B, reduce the metabolism of diosbulbin B in the liver and cause accumulation. In clinical medication, attention should be paid to the drug interaction that can be produced when Chinese medicine containing psoralen/isopsoralen or diosbulbin B is combined.

R969.1

国家自然科学基金资助项目(82174209);广东省普通高校青年创新人才项目(2021KQNCX039)