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目的建立同时测定人血浆中文拉法辛(Ven)和O-去甲基文拉法辛(ODV)的串联质谱方法,研究男性健康志愿者单剂量服用盐酸文拉法辛胶囊,原形药文拉法辛和代谢产物O-去甲基文拉法辛体内药动学行为,评价生物等效性。方法 22名健康受试者采用随机分组自身交叉对照试验设计,二周期分别口服受试制剂和参比制剂盐酸文拉法辛胶囊50 mg,用LC-MS-MS联用法同时测定给药后不同时间点血浆中文拉法辛和O-去甲基文拉法辛的经时血药浓度,采用BAPP软件计算其药动学参数和评价生物等效性。结果血浆样品经蛋白沉淀,在选定的色谱/质谱条件下文拉法辛、O-去甲基文拉法辛与内标及血浆杂质分离良好,文拉法辛、O-去甲基文拉法辛分别在1.99～510μg·L-1(r=0.999 7)和1.99～510μg·L-1(r=0.9997)内线性良好;相对回收率在92.2%～105.9%,日内和日间RSD均小于10.5%。受试制剂和参比制剂的文拉法辛主要药动学参数:tmax分别为(2.2±0.7)和(1.9±0.8)h,ρmax分别为(68.90±23.82)和(69.81±23.73)μg·L-1;t1/2分别为(5.0±1.1)和(4.9±1.6)h;AUC0-24分别为(547.91±288.66)和(592.70±330.70)μg·L-1.h。O-去甲基文拉法辛主要药动学参数:tmax分别为(3.8±1.8)和(4.0±1.6)h,ρmax分别为(73.88±21.18)和(73.96±22.09)μg·L-1;t1/2分别为(8.7±1.8)和(8.9±1.9)h;AUC0-48分别为(1 224.41±239.46)和(1 243.53±287.19)μg.h.L-1;文拉法辛、O-去甲基文拉法辛相对生物利用度分别为(107.8±22.0)%和(99.6±10.7)%。结论用LC-MS-MS同时测定血浆中文拉法辛、O-去甲基文拉法辛浓度,样品处理简单快速,杂质无干扰,定量限低,重复性好,准确度高。两制剂的文拉法辛、O-去甲基文拉法辛的主要药动学参数之间无明显差异,经方差分析和检验,证明两制剂生物等效。
Objective To establish a tandem mass spectrometry method for the simultaneous determination of venlafaxine and o-demethyl-venlafaxine (ODV) in human plasma and to study the effects of venlafaxine hydrochloride capsule Pharmacokinetic Behavior of Farnesin and Metabolite O-desmethyl-venlafaxine for the Evaluation of Bioequivalence. Methods Twenty-two healthy volunteers were randomized to receive a crossover study. Two cycles of oral administration of venlafaxine hydrochloride and 50 mg of venlafaxine hydrochloride were administered orally. The LC-MS-MS method was used to determine the difference Time-lapse blood plasma concentrations of lavazine and o-desmethyl-venlafaxine were calculated using the BAPP software for pharmacokinetic parameters and bioequivalence. RESULTS Plasma samples were protein precipitated and venlafaxine, O-desmethylvenlafaxine was separated from the internal standard and plasma impurities under selected chromatographic / mass spectral conditions. Venlafaxine, O- The linear range was between 1.99 ~ 510μg · L-1 (r = 0.999 7) and 1.99 ~ 510μg · L-1 (r = 0.9997) respectively. The relative recoveries ranged from 92.2% to 105.9% Less than 10.5%. The main pharmacokinetic parameters of venlafaxine were (2.2 ± 0.7) and (1.9 ± 0.8) h, respectively, and ρmax were (68.90 ± 23.82) and (69.81 ± 23.73) μg · (5.0 ± 1.1) and (4.9 ± 1.6) h, respectively; AUC0-24 was (547.91 ± 288.66) and (592.70 ± 330.70) μg · L-1h, respectively; The main pharmacokinetic parameters of O-desmethyl-venlafaxine were: tmax (3.8 ± 1.8) and (4.0 ± 1.6) h, respectively, with ρmax of (73.88 ± 21.18) and (73.96 ± 22.09) μg · L -1 ; t1 / 2 were (8.7 ± 1.8) and (8.9 ± 1.9) h respectively; AUC0-48 were (1 224.41 ± 239.46) and (1 243.53 ± 287.19) μg.hL- The relative bioavailability of demethyl-venlafaxine was (107.8 ± 22.0)% and (99.6 ± 10.7)%, respectively. Conclusions Simultaneous determination of venlafaxine and o-desmethylvenlafaxine in plasma by LC-MS-MS has the advantages of simple and rapid sample processing, no interference of impurities, low quantitation limit, good repeatability and high accuracy. There was no significant difference in the main pharmacokinetic parameters of venlafaxine and o-desmethyllafaxacin between the two preparations. The analysis of variance and test showed that the two preparations were bioequivalent.