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[摘要]
目的 研究盐酸文拉法辛缓释片在Beagle犬体内的药动学和生物等效性。方法 8条健康Beagle犬随机分成2组,采用双周期、双交叉、单剂量分别ig盐酸文拉法辛缓释片受试制剂或参比制剂75 mg,清洗期为1周;建立血浆中盐酸文拉法辛液相色谱-质谱联用(LC-MS/MS)检测方法,进行方法精密度、准确度、提取回收率、基质效应、稳定性方法学验证;测定给药前(0 h)及给药后2、3、4、5、6、8、10、12、14、16、24、36、48、72 h血浆中盐酸文拉法辛血药浓度,运用DAS 2.1.1软件计算其药动学参数,并评价其生物等效性。结果 LC-MS/MS方法学经验证符合检测要求,受试制剂和参比制剂主要药动学参数分别如下:T1/2分别为(7.16±2.34)和(6.95±1.57) h、Cmax分别为(522.89±201.12)和(515.22±159.29)ng/mL、Tmax分别为(10.38±1.69)和(10.50±2.07)h、AUC0-t分别为(8 398.64±3332.86)和(8 050.71±2103.15)ng·h/mL、AUC0-∞分别为(8 701.60±3303.29)和(8 450.01±2273.45)ng·h/mL;以参比制剂为参考,受试制剂AUC0-∞相对生物利用度为(101.0±13.1)%。结论 盐酸文拉法辛缓释片受试制剂与参比制剂在Beagle犬体内具有生物等效性。
[Key word]
[Abstract]
Objective To investigate the pharmacokinetic profiles and bioequivalence of Venlafaxine hydrochloride sustained release tablets.Methods Eight healthy Beagle dogs were ig given Venlafaxine hydrochloride sustained-release tablets or reference tablets of 75 mg in two-cycle, double-crossover and single-dose respectively. A method for the determination of Venlafaxine hydrochloride in plasma by LC-MS/MS was established. The method was validated for precision, accuracy, recovery, matrix effect and stability. The blood concentration of Venlafaxine hydrochloride in plasma was determined before (0 h) and 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, 36, 48, 72 h after administration. The pharmacokinetic parameters were calculated by DAS 2.1.1 and its bioequivalence was evaluated. Results LC-MS/MS methodologies were verified to meet the detection requirements. The main pharmacokinetic parameters of Venlafaxine test and reference preparations were as follows:T1/2, (7.16±2.34) and (6.95±1.57) h; Cmax, (522.89±201.12) and (515.22±159.29) ng/mL; Tmax, (10.38±1.69) and (10.50±2.07) h; AUC0-t, (8 398.64±3 332.86) and (8 050.71±2 103.15) ng·h/mL;AUC0-∞,(8 701.60±3 303.29) and (8 450.01±2 273.45) ng·h/mL, respectively. The relative bioavailability of Venlafaxinewas (101.0±13.1)%。Conclusion Venlafaxine hydrochloride sustained-release tablets have bioequivalence with reference tablets in Beagle dogs.
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[基金项目]
国家重大专项新药创制(2017ZX09201003-006)