Xia Yanming, Dong Ying, Zhao Xiaoli, Di Liuqing, Li Junsong
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Jiangsu Provincial TCM Engineering Technology Research Center of High Efficient Drug Delivery System (DDS), Nanjing, China.
Biopharm Drug Dispos. 2018 Jul;39(7):335-343. doi: 10.1002/bdd.2150. Epub 2018 Aug 12.
Ursodeoxycholic acid (UDCA) is a first-line drug to treat intrahepatic cholestasis of pregnancy (ICP). However, its effects on the fetus are not clearly known. To better guide its clinical use, we aimed to study the mechanism underlying the placental transport of UDCA. The uptake and efflux of UDCA across placental apical membranes were studied using BeWo cells; effects of different exposure durations, UDCA concentrations, temperatures, and inhibitors of transporters were studied. A transwell assay was performed, and UDCA concentration in both fetal and maternal sides was measured using LC-MS/MS. Higher unidirectional transport of UDCA was observed in the basolateral-to-apical direction than in the apical-to-basolateral direction. Ko143 and verapamil, which are typical inhibitors of efflux transporters, significantly increased UDCA transport from different directions. UDCA uptake from the apical membrane of BeWo cells was time-dependent, but sodium-independent. It was inhibited by inhibitors of energy metabolism and of organic anion transporters, indicating an active transport mechanism. UDCA uptake from the apical membranes of BeWo cells could be mediated by organic anion-transporting polypeptides, whereas its efflux could be mediated by breast cancer resistance protein and multidrug resistant protein 3. The results of the present study may provide a basis for UDCA use in pregnancy.
熊去氧胆酸（UDCA）是治疗妊娠期肝内胆汁淤积症（ICP）的一线药物。然而，其对胎儿的影响尚不清楚。为了更好地指导其临床应用，我们旨在研究UDCA胎盘转运的潜在机制。使用BeWo细胞研究UDCA跨胎盘顶膜的摄取和流出；研究了不同暴露时间、UDCA浓度、温度和转运体抑制剂的影响。进行了Transwell实验，并使用液相色谱-串联质谱法（LC-MS/MS）测量胎儿侧和母体侧的UDCA浓度。观察到UDCA在基底外侧到顶侧方向的单向转运高于顶侧到基底外侧方向。外流转运体的典型抑制剂Ko143和维拉帕米显著增加了UDCA从不同方向的转运。BeWo细胞顶膜对UDCA的摄取具有时间依赖性，但不依赖于钠。它受到能量代谢抑制剂和有机阴离子转运体抑制剂的抑制，表明存在主动转运机制。BeWo细胞顶膜对UDCA的摄取可能由有机阴离子转运多肽介导，而其流出可能由乳腺癌耐药蛋白和多药耐药蛋白3介导。本研究结果可能为UDCA在妊娠期的应用提供依据。
