伊伐布雷定及其代谢物的血药浓度测定及人体药动学研究

Determination of Ivabradine and its Metabolite in Human Plasma and Pharmacokinetic Study

目的:建立伊伐布雷定(IVA)及其活性代谢产物N-去甲基伊伐布雷定(M1)人体血药浓度的HPLC-MS/MS同时测定方法,研究盐酸伊伐布雷定片经健康受试者口服后IVA及M1的人体药代动力学特征。方法:12名健康受试者单次口服盐酸伊伐布雷定片2.5 mg、5 mg和7.5 mg,多次口服5 mg后,采用HPLC-MS/MS测定不同时间点血浆中IVA和M1浓度,并计算其主要药动学参数。结果:IVA和M1血药浓度标准曲线线性范围分别为0.03～80 ng.mL-1和0.03～10 ng·mL-1。单次给药2.5、5、7.5 mg后IVA的Cmax分别为(9.661±3.832)、(20.63±9.31)、(34.95±19.46)ng·mL-1,AUC0-48分别为(42.16±19.53)、(85.86±44.85)、(133.6±65.7)μg·h·L-1;M1的Cmax分别为(1.007±0.189)、(2.683±0.675)、(4.064±1.172)ng·mL-1,AUC0-48分别为(10.78±1.35)、(26.02±4.91)、(36.24±7.90)μg·h·L-1。多次给药5 mg后IVA的稳态平均血药浓度Cav为(6.494±2.385)ng.mL-1,稳态血药浓度波动度DF为(3.3±0.7),累积常数RAUC为(1.1±0.2);M1的Cav为(1.959±0.186)ng.mL-1,DF为(1.4±0.3),RAUC为(1.5±0.2)。结论:建立的人血浆中IVA和M1的LC-MS/MS同时测定方法适用于人体药代动力学研究。单次给药后,在2.5～7.5 mg范围内IVA和M1均呈线性药动学特征;多次给药5 mg后,IVA人体内的暴露量约增加10%,M1人体内的暴露量约增加50%。

Objective：To establish an HPLC-MS/MS method for the simultaneous determination of ivabradine（IVA） and its active metabolite N-desmethylivabradine（M1） in human plasma and to investigate their pharmacokinetics after oral administration of ivabradine hydrochloride tablets in healthy volunteers.Methods：Twelve healthy Chinese volunteers were given single dose of 2.5 mg,5 mg and 7.5 mg and multiple doses of 5 mg ivabradine hydrochloride tablets.Plasma samples were analyzed by HPLC-MS/MS.The pharmacokinetics of IVA and M1 were evaluated.Results：The calibration curves were linear over the range of 0.03~80 ng.mL-1 for IVA and 0.03~10 ng.mL-1 for M1,respectively.After single dose of 2.5,5 and 7.5 mg,the Cmax of IVA were（9.661±3.832）,（20.63±9.31） and（34.95±19.46） ng.mL-1,the AUC0-48 of IVA were（42.16±19.53）,（85.86±44.85） and（133.6±65.7） μg.h.L-1;the Cmax of M1 were（1.007±0.189）,（2.683±0.675） and（4.064±1.172） ng.mL-1,the AUC0-48 of M1 were（10.78±1.35）,（26.02±4.91） and（36.24± 7.90） μg.h.L-1,respectively.After multiple doses of 5 mg,the Cav,DF and RAUC of IVA were（6.494±2.385） ng.mL-1,（3.3±0.7） and（1.1±0.2）;the Cav,DF and RAUC of M1 were（1.959±0.186） ng.mL-1,（1.4±0.3） and（1.5 ±0.2）,respectively.Conclusion：The developed method can be successfully applied to the pharmacokinetic study and therapeutic drug monitoring of IVA and M1.AUC and Cmax values for both IVA and M1 increased linearly with IVA dose after single dose over the dose range of 2.5 ~7.5 mg.A slight accumulation of IVA and M1 after multiple doses was observed.