Identification and characterization of nucleoside transporters that participate in placental permeation of drugs

利巴韦林，一种抗病毒药物，被证明通过CNT3和ENT1在人绒毛膜癌（Bewo）细胞中运输。然后我们研究了核苷转运体的每个亚型的特征。利用表达人核苷转运体的非洲爪蟾卵母细胞，研究表明利巴韦林对钠依赖性转运体（CNT）具有较高的亲和力（~ 20 μM），对钠非依赖性转运体（ENT）具有较低的亲和力（~ mM）。由于有报道称CNT和ENT都在胎盘上皮细胞的刷状边界膜中表达，我们测量了同时表达hCNT3和hENT1（共表达卵母细胞）的卵母细胞对利巴韦林的摄取。共表达卵母细胞对利巴韦林的摄取低于仅表达hCNT3的卵母细胞。这些结果表明，利巴韦林在细胞内的浓度是通过CNT的摄取和耳鼻喉部的外排来维持的，利巴韦林通过胎盘的渗透不是向胎儿侧集中的。另一方面，在肠道中，CNT和ENT分别在刷状边缘膜和基底外膜上表达，这些转运蛋白也有助于利巴韦林的吸收。在肠内，利巴韦林通过刷状边缘膜被集中吸收，然后通过基底外膜的扩散进入血流。

Ribavirin, an antivirus agent, was shown to be transported via CNT3 and ENT1 in human choriocarcinoma (Bewo) cells. Then we investigated characteristics of each subtype of the nucleoside transporters. Using Xenopus laevis oocytes expressing human nucleoside transporters, it was suggested that ribavirin has relatively higher affinity (〜20 μM) to sodium-dependent transporters (CNT) and lower affinity (〜mM) to sodium-independent transporters (ENT). Since it is reported that both CNT and ENT express in the brush border membrane of the placental epithelial cells, we measured the uptake of rebavirin by the oocytes expressing both hCNT3 and hENT1 (co-expressing oocyte). The uptake of ribavirin by co-expressing oocytes was lower than that by the oocytes that expressing only hCNT3. These results suggest that the concentration of ribavirin in the cells is maintained by the uptake via CNT and efflux via ENT and permeation of ribavirin through the placenta is not concentrative toward fetal side.On the other hand, it was suggested that in the intestine, in which CNT and ENT express in brush border membrane and basolateral membrane, respectively, these transporters also contribute to the absorption of ribavirin. In the intestine, rebavirin was suggested to be taken up by concentrative manner through the brush border membrane, and then fluxed into blood flow by facilitated diffusion through the basolateral membrane.