LC-MS/MS法测定人血浆中拉米夫定浓度及其生物等效性研究

Determination of lamivudine in human plasma by LC-MS/MS and its bioequivalence

目的建立测定人血浆中拉米夫定浓度的LC-MS/MS方法,并评价拉米夫定片在健康志愿者体内的相对生物利用度及2种制剂间的生物等效性。方法 24名健康男性志愿者随机分组、自身双交叉,分别单剂量口服100 mg拉米夫定试验制剂和参比制剂,LC-MS/MS法测定血浆中拉米夫定浓度,采用WinNonlin 6.1软件计算药动学参数。结果拉米夫定在20.48～5 000μg L-1与峰面积呈良好的线性关系,最低定量限(LLOQ)为20.48μg L-1。口服100 mg拉米夫定参比制剂和试验制剂后的主要药动学参数如下:Cmax分别为(1 152.6±326.4)和(1 032.4±319.7)μg L-1;tmax分别为(0.93±0.30)和(1.07±0.47)h;t1/2分别为(3.4±0.7)和(3.3±0.6)h;AUC0～16 h分别为(3 811.9±870.2)和(3 753.6±1 067.0)μg h L-1;AUC0～∞分别为(3 958.9±871.3)和(3 914.8±1 087.0)μg h L-1。试验制剂的相对生物利用度为(98.2±17.0)%。结论本方法简单、快速、灵敏、准确,可用于人血浆中拉米夫定浓度的测定。试验制剂与参比制剂具有生物等效性。

Objective To establish an LC-MS/MS method to determine lamivudine in human plasma and to study the bioavailability and bioequivalence of the test and reference lamivudine tablets in healthy male volunteers.Methods A single oral dose（100 mg） of test tablets or reference tablets was given to each volunteer according to an open randomized crossover study.The concentrations in the plasma were determined by LC-MS/MS method.The pharmacokinetic parameters were calculated by WinNonlin 6.1 software.Results The calibration curve of lamivudine showed good linearity at 20.48-5 000 μg L-1.The LLOQ of lamivudine was 20.48 μg L-1.The main pharmacokinetic parameters of lamivudine were as follows： Cmax（1 152.6±326.4） and（1 032.4±319.7） μg L-1;tmax（0.93±0.30） and（1.07±0.47） h;t1/2（3.4±0.7） and（3.3±0.6） h;AUC0 ～ 16 h（3 811.9±870.2） and（3 753.6±1 067.0） μg h L-1;AUC0 ～∞（3 958.9±871.3） and（3 914.8±1 087.0） μg h L-1for the reference and test preparations,respectively.The relative bioavailability of test tablets was（98.2±17.0）%.Conclusion The method is simple,rapid,sensitive and accurate,which can be used to detect the concentration of lamivudine in human plasma.The two lamivudine preparations are bioequivalent.