基于人胎盘体外循环灌注模型的拉米夫定体外胎盘透过率研究

Placental Transfer of Lamivudine in an ex vivo Human Placental Perfusion Model

目的:评估拉米夫定的体外胎盘透过率。方法:建立人胎盘体外循环灌注模型,在母体灌流液中加入试验药物拉米夫定(1500 ng·ml^(-1))和阳性标记物安替比林(100μg·ml^(-1)),循环灌注3 h。应用UFLC-MS/MS法于循环开始0,10,20,30,45,60,75,90,120,150和180 min分别测定拉米夫定浓度,计算胎盘透过率。同时在循环过程中检测灌流液pH、pO2、hCG、葡萄糖消耗量、乳酸生成量、子体池损耗以及安替比林透过率,评估灌注过程中胎盘活性。结果:成功建立人胎盘体外循环灌注模型10例。安替比林和拉米夫定的平均胎盘透过率分别为(28.91±3.58)%和(10.23±2.93)%,拉米夫定的清除指数为(0.36±0.10)。结论:体外实验提示,拉米夫定可少量透过胎盘,但该暴露量是否增加不良胎儿结局的发生风险仍有待更多的临床研究以确证。

Objective:To determine the ex vivo human placental transfer of lamivudine from maternal circulation to fetal circulation.Methods:Perfusion studies were performed on an ex vivo human placenta perfusion model.The placental cotyledons were perfused for 180 min with lamivudine(1500 ng·ml^(-1)).Antipyrine(100μg·ml^(-1))was used as a positive marker to evaluate the integrity of the circuit.Samples were collected at 0,10,20,30,45,60,75,90,120,150 and 180 min and determined by UFLC-MS/MS.Main transfer parameters including fetal transfer rate and evaluation indicators including fetal volume loss were assessed.Integrity and viability of the placenta were determined by measuring fetal volume loss,pH,pO2,hCG,glucose consumption,lactate production and fetal transfer rate of antipyrine during the perfusion experiments.Results:Ten experimental perfusion set-ups of human placenta were completed.The maternal-fetal transport rate for antipyrine and lamivudine was 28.91%±3.58%and 10.23%±2.93%,respectively.The clearance index of lamivudine was 0.36±0.10.Conclusion:The results indicate that a small quantity of lamivudine crosses mature human placenta.Therefore,long-term outcome of exposed fetuses should be evaluated before treating pregnant women with lamivudine.