体外探讨五味子乙素对大鼠肝微粒体CYP3A的影响及其作用机制

目的通过体外药物代谢实验探讨五味子乙素对CYP3A活性的影响,并探讨其作用机制。方法以大鼠肝微粒体为载体,选取咪达唑仑为药物"探针",建立高效液相色谱法(HPLC)检测五味子乙素对肝微粒体代谢咪达唑仑的影响,体外给药测定其IC50值以及相关酶动力学参数,并推测其可能的作用机制。结果孵育体系内源性物质不干扰测定,方法快捷、稳定、灵敏度高。结果显示五味子乙素呈剂量依赖性抑制体外肝微粒体咪达唑仑代谢,其IC50为5.50g.L-1,据此计算其Ki为4.32mol·L-1。结论五味子乙素体外抑制大鼠肝微粒体CYP3A活性,其作用机制为可逆性抑制,属于非竞争性抑制类型。

Investigation on the effect of Schisandrin B in rat liver microsomal CYP3A activity and its inhibition mechanism in vitro

Aim To investigate the inhibitory effects of Schisandrin B(Sch B)on cytochrome P450(CYP3A)activity and its possible inhibition mechanism in vitro.Methods Rat liver microsomes as the carrier and midazolam as the probe-drug,the influence of Sch B on liver microsomal metabolism was detected by High Performance Liquid Chromatography(HPLC).Administering Sch B in vitro,the IC50 value and associated kinetic parameters were determined,and then its possible mechanism was speculated.Results The determination was not interfered by endogenous substances of the incubation system,and the method with high sensitivity was fast and stable.The current results showed that Sch B inhibited CYP3A activity with IC50 values of 5.50 g·L-1 and produced concentration-dependent inhibition of MDZ metabolite formation in rat liver microsomes(in vitro)in comparison with vehicle-treated microsomes.Then the Ki value of 4.32 mol·L-1 was calculated on these results.Conclusion The inhibition of CYP3A activity in rat liver microsomes by Sch B is reversible,and mostly attributed to a noncompetitive inhibition.