维拉帕米对替芬泰大鼠体内药代动力学的作用

Effects of verapamil on pharmacokinetics of Y101 in vivo in rats

目的建立测定大鼠血浆中替芬泰及代谢产物M8、M9浓度的LC-MS/MS分析方法,研究P-gp抑制剂维拉帕米对替芬泰(P-gp底物)大鼠体内药代动力学的影响。方法SD大鼠灌胃给药,对照组给予60 mg·kg^(-1)替芬泰,实验组给予60 mg·kg^(-1)替芬泰联用25 mg·kg^(-1)维拉帕米。采用LC-MS/MS方法测定给药后不同时间替芬泰及代谢物的血药浓度,非房室模型法计算药动学参数。结果同时测定大鼠血浆中替芬泰、M8和M9的LC-MS/MS方法通过了严格的方法学验证。与对照组相比,联用维拉帕米的实验组大鼠体内替芬泰和M9的AUC 0-t升高,分别为对照组的1.71倍和1.58倍;替芬泰和M9清除率CL降低,约为对照组的60%;M8的AUC 0-t和CL无显著改变。结论P-gp抑制剂维拉帕米可明显提高替芬泰及代谢物的体内暴露水平,提示临床两者合用需要调整给药剂量。

Aim To develop a liquid chromatography electrospray-ionization tandem mass spectrometry(LC-MS/MS)method for simultaneous determination of bentysrepinine(Y101)and its metabolites M8 and M9 in rat plasma and to investigate the effect of verapamil,an inhibitor of P-glycoprotein(P-gp),on the pharmacokinetics of Y101,a substrate of P-gp,in rats.Methods SD rats were divided randomly into two groups:(1)Y101 only as a control group,received an oral dose of 60 mg·kg^(-1)Y101;(2)Verapamil plus Y101 as an experimental group,received an oral dose of 60 mg·kg^(-1)Y101 in combination of 25 mg·kg^(-1)verapamil.The plasma concentrations of Y101 and its metabolites were determined by LC-MS/MS method after intragastric administration,and the pharmacokinetic parameters were calculated using non-compartmental analysis.Results We successfully developed and fully validated a LC-MS/MS method,which simultaneously determined the concentration of Y101 and its metabolites in rat plasma.The AUC 0-t for Y101 and M9 in experimental group increased to 1.71-fold and 1.58-fold in comparison of control group.At the same time,the plasma clearance of Y101 and M9 decreased to 60%of control.However,we did not find any difference in AUC 0-t and plasma clearance for M8 between two groups.Conclusions The validated LC-MS/MS method is sensitive and rapid for the determination of Y101 and its metabolites in rat plasma and was successfully applied to the pharmacokinetic study in rats.Verapamil,a P-gp inhibitor,significantly increases the exposure of Y101 and its metabolites in vivo,indicating the adjustment of Y101 dosage for combined administration is needed in clinical practice.