鸦胆子和水飞蓟主要活性成分对苯妥英代谢的抑制作用研究

Inhibitory effect of the main active components of Brucea javanica and Silythistle on the metabolism of Phenytoin

目的探讨鸦胆子和水飞蓟主要活性成分对人肝微粒体催化苯妥英代谢的抑制作用。方法采用超高效液相色谱—串联质谱(UPLC-MS/MS)法,选择ESI正离子模式测定苯妥英的代谢产物5-(4羟基苯基)-5-苯基乙内酰脲(p-HPPH)生成速率。利用产物p-HPPH生成速率的改变评价鸦胆子苦醇、鸦胆子素D、水飞蓟宾A和水飞蓟宾B对人肝微粒体催化的苯妥英代谢的抑制作用。结果水飞蓟宾A对人肝微粒体催化的苯妥英代谢具有强抑制作用,半抑制浓度(IC50)为7.670μmol/L。水飞蓟宾B具有中等抑制作用,IC50为15.490μmol/L。而鸦胆子苦醇和鸦胆子素D无明显抑制作用。结论临床用药中应避免水飞蓟制品与抗癫痫药苯妥英联合应用,以免药物相互作用引发临床不良发应。

Objective To evaluate whether the main components of Brucea and Milk thistle will inhibit Phenytoin metabolism in human liver microsomes.Methods Ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)was used to determine the formation rate of 5-(4-hydroxyphenyl)-5-phenylacetonitroide(P-HPPH),a metabolite of phenytoin,in ESI positive mode.The alteration of p-HPPH formation rate was employed to evaluate the inhibitory effect of brusatol,bruceine D,silybin A and silybin B on Phenytoin metabolism by human liver microsomes.Results Silybin A potently inhibited human liver microsomes catalyzed phenytoin metabolism with an IC50 values of 7.67μmol/L.Silybin B was a moderate inhibitor with an IC50 values of 15.49μmol/L.Brusatol and bruceine D showed no significant inhibitory effect.Conclusion In order to avoid drug interaction caused by adverse clinical response,the combination of silybin A and silybin B with antiepileptic drug phenytoin should be avoided.