穗花杉双黄酮对CYP2C8酶活性的影响

Effects of amentoflavone on the enzyme activity of CYP2C8

目的考察穗花杉双黄酮对CYP2C8代谢酶活性的影响。方法构建体外人肝微粒体代谢体系,以紫杉醇为探针底物,考察穗花杉双黄酮对CYP2C8活性的影响。大鼠连续7 d尾静脉注射穗花杉双黄酮3 mg·kg^(-1),考察紫杉醇在大鼠体内的药动学。采用HPLC-MS/MS法分别测定体外代谢体系中6α-羟基紫杉醇及大鼠血浆中紫杉醇的含量。结果穗花杉双黄酮在体外对CYP2C8有较强的抑制效应,半数抑制浓度(IC_(50))=0.2765μmol·L^(-1),抑制常数(Ki)=0.034μmol·L^(-1),抑制类型为混合型抑制。给予3 mg·kg^(-1)穗花杉双黄酮不会通过与CYP2C8的直接相互作用而改变紫杉醇的药动学。结论穗花杉双黄酮为人肝微粒体中CYP2C8代谢酶的强抑制剂,但在体内对CYP2C8的活性无影响。

OBJECTIVE To investigate the effect of amentoflavone on the activity of CYP2C8 metabolizing enzyme.METHODS The effect of amentoflavone on CYP2C8 activity was investigated in the metabolic system in vitro,using paclitaxel as the probe substrate.The pharmacokinetics of paclitaxel was investigated by tail vein injection of amentoflavone(3 mg·kg^(-1))for 7 consecutive days.The HPLC-MS/MS method was applied to determine the content of 6α-hydroxy paclitaxel in the metabolic system in vitro as well as in rat plasma,respectively.RESULTS In vitro,amentoflavone had a strong inhibitory effect on CYP2C8,with an IC_(50)of 0.2765μmol·L^(-1)and a Ki of 0.034μmol·L^(-1),and the type of inhibition was mixed inhibition.3 mg·kg^(-1)amentoflavone did not alter pharmacokinetics of paclitaxel through direct interaction with CYP2C8.CONCLUSION Amentoflavone is a strong inhibitor of CYP2C8 metabolizing enzymes in human liver microsomes,but has no effect on the activity of CYP2C8 in vivo.