Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.
Pharmacy Practice Department, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
AAPS J. 2020 Oct 25;22(6):138. doi: 10.1208/s12248-020-00516-2.
Treatment guidelines recommend continuation of combination antiretroviral therapy (cART) throughout pregnancy for all women living with human immunodeficiency virus (HIV). Many of these drugs are substrates of transporters expressed in the placenta and therefore play a role in fetal exposure. As placental transporters can be impacted by both HIV infection and drug therapy, our objective was to explore the impact of HIV infection and cART on transporter expression. Drug transporter expression was examined in human placental samples collected from women with HIV (n = 25) and from healthy HIV(-) controls (n = 23). The effect of exposure to drugs commonly used in cART during pregnancy was examined in vitro in placental villous explants obtained from healthy women. Gene expression was measured via qRT-PCR. Several ABC (ABCG2, ABCC1,2,4) and SLC (SLC21A9, SLC22A1,3,11) transporters were significantly downregulated in placentas isolated from HIV(+) women as compared with HIV(-) controls (p < 0.05-0.001), while ABCB1 and SLC21A12 were significantly upregulated (p < 0.001). Twenty-four to 48-h exposure of human placental explants to agents used in cART resulted in significant upregulation of ABCB1 and downregulation of SLC22A11. Our findings suggest that transplacental transport may be compromised during HIV infection due to altered expression of clinically important transporters. Furthermore, in vitro results indicate that cART imposes significant alterations in placental transporters but not all changes are consistent with findings in the placenta from HIV(+) women, indicating disease effects. As this may impact in utero-fetal exposure to clinically used medications, further studies are needed to determine the overall impact on maternal-fetal transfer.
治疗指南建议所有感染人类免疫缺陷病毒 (HIV) 的孕妇继续接受联合抗逆转录病毒治疗 (cART)。这些药物中有许多是在胎盘表达的转运体的底物，因此在胎儿暴露中起作用。由于胎盘转运体可能受到 HIV 感染和药物治疗的双重影响，我们的目标是探讨 HIV 感染和 cART 对转运体表达的影响。我们检查了来自 HIV 阳性 (n=25) 和健康 HIV(-) 对照 (n=23) 女性的胎盘样本中的药物转运体表达。在来自健康女性的胎盘绒毛外植体中体外检查了在怀孕期间常用的药物治疗对 cART 的暴露的影响。通过 qRT-PCR 测量基因表达。与 HIV(-) 对照组相比，从 HIV(+) 女性分离的胎盘组织中几种 ABC（ABCG2、ABCC1、2、4）和 SLC（SLC21A9、SLC22A1、3、11）转运体的表达显著下调（p<0.05-0.001），而 ABCB1 和 SLC21A12 则显著上调（p<0.001）。cART 中使用的药物对人胎盘外植体 24-48 小时的暴露导致 ABCB1 显著上调和 SLC22A11 下调。我们的研究结果表明，由于临床重要转运体表达改变，HIV 感染期间可能会损害胎盘转运。此外，体外结果表明，cART 对胎盘转运体造成重大改变，但并非所有变化都与 HIV(+) 女性胎盘一致，表明疾病的影响。由于这可能会影响到胎儿对临床用药的暴露，因此需要进一步研究以确定对母婴转移的整体影响。
