Functional Role of P-Glycoprotein and Binding Protein Effect on the Placental Transfer of Lopinavir/Ritonavir in the Ex Vivo Human Perfusion Model
Functional Role of P-Glycoprotein and Binding Protein Effect on the Placental Transfer of Lopinavir/Ritonavir in the Ex Vivo Human Perfusion Model
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DOI：
10.1155/2009/726593
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发表时间：
2009-01-01
影响因子：
1.9
通讯作者：
Gil, Sophie
中科院分区：
文献类型：
--
作者：
Ceccaldi, Pierre-Francois;Gavard, Laurent;Gil, Sophie
目标。研究不同白蛋白浓度下P-糖蛋白（P-糖蛋白、ABCB1、MDR1）功能对洛匹那韦与利托那韦胎盘转移的影响。方法。子叶灌注不同白蛋白浓度（10、30、40 g/L）的洛匹那韦、利托那韦和内对照安替吡林。每次实验对照期结束后，在灌注中期（45分钟）加入p -糖蛋白抑制剂环孢素A。比较两期胎儿移植率（FTR）和清除率指数（CLI）。结果。在对照期，随着白蛋白浓度从10 g/L增加到30、40 g/L，洛匹那韦的清除率从0.401 +/- b0.058下降到0.007 +/- 0.027。当添加生理白蛋白浓度的环孢素A时，洛匹那韦的清除率显著提高10.3倍（95% CI差[-0.156,-0.002],P = 0.046），利托那韦呈阳性。结论。即使在高白蛋白浓度下，抑制胎盘p糖蛋白也会增加洛匹那韦的胎盘转运，这表明这种外排泵积极地减少了药物的胎盘转运。这一机制可能在胎儿暴露于母体抗逆转录病毒治疗中发挥作用。版权所有(C) 2009皮埃尔-弗朗索瓦·塞卡尔迪等。
Aims. To study the influence of P- glycoprotein (P-glycoprotein, ABCB1, MDR1) function on placental transfer of lopinavir with ritonavir at different albumin concentrations. Methods. Cotyledons were perfused with lopinavir, ritonavir, and the internal control antipyrin, at various albumin concentrations (10, 30, 40 g/L). After the control phase of each experiment, the P-glycoprotein inhibitor ciclosporin A was added at middle perfusion (45 minutes). Fetal Transfer Rate (FTR) and Clearance Index (CLI) were compared between the 2 phases. Results. In the control phase, the clearance index of lopinavir decreased from 0.401 +/- b0.058 to 0.007 +/- 0.027, as albumin concentrations increased from 10 g/L to higher concentrations (30, 40 g/L). When adding ciclosporin A at physiological albumin concentrations, the clearance index of lopinavir increased significantly 10.3 fold (95% of CI difference [-0.156, -0.002], P =.046) and became positive for ritonavir. Conclusions. Even at high albumin concentrations, inhibition of placental P-glycoprotein increased placental transfer of lopinavir, suggesting that this efflux pump actively reduces placental transfer of the drug. This mechanism may play a role in fetal exposure to maternal antiretroviral therapy. Copyright (C) 2009 Pierre-Francois Ceccaldi et al.