Ceccaldi Pierre-Francois, Gavard Laurent, Mandelbrot Laurent, Rey Elisabeth, Farinotti Robert, Treluyer Jean-Marc, Gil Sophie
Department of Obstetrics and Gynecology, Louis Mourier Hospital, AP-HP, Paris 7 University, 92701 Colombes, France.
Obstet Gynecol Int. 2009;2009:726593. doi: 10.1155/2009/726593. Epub 2009 May 18.
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 +/- 0.058 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.
目的。研究P-糖蛋白（P-糖蛋白，ABCB1，MDR1）功能在不同白蛋白浓度下对洛匹那韦与利托那韦胎盘转运的影响。方法。在不同白蛋白浓度（10、30、40 g/L）下，用洛匹那韦、利托那韦和内对照安替比林灌注胎盘小叶。在每个实验的对照阶段后，在灌注中期（45分钟）加入P-糖蛋白抑制剂环孢素A。比较两个阶段的胎儿转运率（FTR）和清除指数（CLI）。结果。在对照阶段，随着白蛋白浓度从10 g/L增加到更高浓度（30、40 g/L），洛匹那韦的清除指数从0.401±0.058降至0.007±0.027。在生理白蛋白浓度下加入环孢素A时，洛匹那韦的清除指数显著增加10.3倍（95%CI差异[-0.156，-0.002]，P = 0.046），利托那韦的清除指数变为正值。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，表明这种外排泵会主动降低药物的胎盘转运。这种机制可能在胎儿暴露于母体抗逆转录病毒治疗中起作用。
