盐酸文拉法辛缓释片人体药动学和生物等效性研究

Pharmacokinetics and bioequivalance of domestic venlafaxine in healthy Chinese volunteers

目的:建立测定文拉法辛血浆药物浓度的HPLC荧光检测法,研究盐酸文拉法辛缓释片在人体的药动学和评价生物等效性。方法:48例青年健康志愿受试者(单次给药24例,多次给药24例),分别单次和多次交叉口服文拉法辛参比制剂75mg和受试制剂75mg,采用HPLC法测定给药后不同时间点血浆中文拉法辛和O-去甲文拉法辛经时血药浓度,采用DAS 2.0进行药动学参数计算。结果:单次和多次口服盐酸文拉法辛缓释片的血药浓度-时间曲线符合一室开放模型。单次口服受试制剂和参比制剂后文拉法辛的T_(max)分别为(6.5±1.9)与(6.3±1.4)h,t_(1/2)分别为(11.6±4.9)与(11.7±4.3)h,AUC_(0～t)分别为(1840.0±1153.1)和(1956.0±1201.2)μg·h·L^(-1);O-去甲文拉法辛的T_(max)分别为(12.0±6.0)与(10.3±6.1)h,t_(1/2)分别为(1 8.9±4.8)与(20.3±6.2)h,AUC_(0～t)分别为(1356.8±344.1)和(1382.8±287.3)μg·h·L^(-1);文拉法辛和O-去甲文拉法手的生物利用度分别为(94.3±13.3)%和(99.3±20 4)%。多次口服受试制剂和参比制剂6d后文拉法辛的AUC_(ss)分别为(1488.9±863.3)和(1630.7±962.2)μg·h·L^(-1),T_(max)分别为(7.0±1.6)与(6.7±1.8)h,DF分别为(114.63±27.05)和(110.94±24.25);O-去甲文拉法辛的AUC_(ss)分别为(528.3±220.6)和(568.3±251.1)μg·h·L^(-1),T_(max)分别为(7.7±2.1)与(7.3±1.9)h,DF分别为(70.12±21.63)和(71.67±24.27);文拉法辛和O-去甲文拉法辛的生物利用度分别为(93.2±17.7)%和(95.9±17.0)%。结论:经方差分析和t检验,证明两制剂生物等效。

Objective： To develop and validate a HPLC-fluorometric method for determining venlafaxine and O-demethyl venlafaxine in human plasma and to study the pharmaeokinetie profiles and bioequivalence of venlafaxine tablets. Methods： A single oral dose （75 mg） and multi-oral dose of test and reference venlafaxine were given to 48 healthy male volunteers in an open randomized cross-over study. Venlafaxine and O-demethyl venlafaxine concentrations in plasma were determined by HPLC method. The pharmaeokinetie parameters as well as relative bioavailability were measured. Results： The concentration-time curves of venlafaxine were described by a one-compartment open model. The main pharmaeokinetie parameters of venlafaxine test and reference preparations were as follows after a single dose： Tmax （6.5±1.9） and （6.3±1.4）h, t1/2（11.6±4.9） and （11.7±4.3） h; AUC0-1（1 840.0±1 153.1） and （ 1 956.0 ± 1 201.2） μg·h·L^-1 , respectively. The main pharmaeokinetie parameters of O-demethyl venlafaxine were as follows after a single dose ： Tmax （ 12.0 ± 6.0） and （ 10.3 ± 6.1 ） h, t1/2 （ 18.9 ± 4.8 ） and （20.3±6.2） h, AUC0-t（1 356.8±344.1） and （1 382.8±287.3）μg·h·L^-1, respectively. The relative bioavailability of venlafaxine and O-demethyl venlafaxine were （94.3 ± 13.3） % and （99.3 ± 20.4） %. The main pharmaeokinetie parameters of venlafaxine were as follows after the multi-dose of venlafaxine test or reference preparations ： AUCss （ 1 488.9 ± 863.3 ） and （ 1 630.7 ± 962.2） μg·h·L^-1, Tmax（7.0±1.6） and （6.7±1.8） h, DF （114.63±27.05） and （110.94±24.25）, respectively. The main pharmaeokinetie parameters of O-demethyl venlafaxine were as follows after the multi-dose of venlafaxine test or reference preparations ： AUCss （ 528.3±220.6 ） and （568.3 ± 251.1 ） μg·h·L^-1, Tmax （7.7 ±2.1） and （7.3±1.9） h, DF （70.12±21.63） and （71.67±24.27）, respectively. There was no significant difference between the two formulations. The relative bioavailability of venlafaxine and O-demethyl venlafaxine were （93.2 ± 17.7） % and （95.9 ± 17.0） %. Conclusion： The result of the statistical analysis showed that the two formulations were bioequivalent.