Sudhakaran Sreeja, Ghabrial Hany, Nation Roger L, Kong David C M, Gude Neil M, Angus Peter W, Rayner Craig R
Facility for Anti-Infective Drug Development and Innovation, Monash University, 381 Royal Parade, Parkville, 3052, Melbourne, Australia.
Antimicrob Agents Chemother. 2005 Mar;49(3):1023-8. doi: 10.1128/AAC.49.3.1023-1028.2005.
The protease inhibitor (PI) indinavir may be used in the management of human immunodeficiency virus (HIV) infection during pregnancy. Poor maternal-to-fetal transfer of indinavir has been reported previously, but the mechanisms of transfer remain unknown. The bidirectional transfer of indinavir was assessed in dually perfused, isolated human placentae. Term placentae (n = 5) were obtained from non-HIV-infected pregnant women. To investigate transport mechanisms, the steady-state transfer of indinavir was compared to those of antipyrine (a marker of passive diffusion) and [(3)H]vinblastine (a marker of P-glycoprotein [P-gp] transport) in the maternal-to-fetal and fetal-to-maternal directions in each placenta. Indinavir and antipyrine perfusate concentrations were determined by using reverse-phase, high-performance liquid chromatography; [(3)H]vinblastine concentrations were measured by liquid scintillation. The antipyrine transfer clearance in each direction did not differ (P = 0.76), a finding consistent with passive diffusion. However, the maternal-to-fetal transfer clearance of vinblastine, normalized to that of antipyrine (clearance index) (0.31 +/- 0.05), was significantly lower than the fetal-to-maternal clearance index of vinblastine (0.67 +/- 0.17; P = 0.017), suggesting the involvement of placental P-gp. Similarly, the maternal-to-fetal clearance index of indinavir (0.39 +/- 0.09) was significantly lower than its fetal-to-maternal clearance index (0.97 +/- 0.12; P < 0.001). These results represent the first evidence for differential transfer of a xenobiotic in the intact human placenta. The use of transport modulators to increase the maternal-to-fetal transfer of PIs as a possible strategy to reduce mother-to-child transmission of HIV warrants investigation.
蛋白酶抑制剂茚地那韦可用于孕期人类免疫缺陷病毒（HIV）感染的管理。此前有报道称茚地那韦从母体到胎儿的转运较差，但其转运机制仍不清楚。在双灌注、离体的人胎盘中评估了茚地那韦的双向转运。足月胎盘（n = 5）取自未感染HIV的孕妇。为了研究转运机制，在每个胎盘的母体到胎儿和胎儿到母体方向上，将茚地那韦的稳态转运与安替比林（被动扩散标志物）和[³H]长春碱（P-糖蛋白[P-gp]转运标志物）的转运进行了比较。使用反相高效液相色谱法测定茚地那韦和安替比林灌注液浓度；通过液体闪烁法测量[³H]长春碱浓度。安替比林在每个方向上的转运清除率没有差异（P = 0.76），这一结果与被动扩散一致。然而，长春碱的母体到胎儿转运清除率，以安替比林的清除率为标准进行归一化（清除指数）（0.31±0.05），显著低于长春碱的胎儿到母体清除指数（0.67±0.17；P = 0.017），提示胎盘P-gp参与其中。同样，茚地那韦的母体到胎儿清除指数（0.39±0.09）显著低于其胎儿到母体清除指数（0.97±0.12；P < 0.001）。这些结果是外源性物质在完整人胎盘中差异转运的首个证据。使用转运调节剂来增加蛋白酶抑制剂从母体到胎儿的转运，作为减少HIV母婴传播的一种可能策略，值得研究。
