PDF(Pubmed)
Abstract：
In human pregnancy, metformin administered to the mother crosses the placenta resulting in metformin exposure to the fetus. However, the effects of metformin exposure on the fetus are poorly understood and difficult to study in humans. Pregnant sheep are a powerful large animal model for studying fetal physiology. The objective of this study was to determine if maternally administered metformin at human dose-equivalent concentrations crosses the ovine placenta and equilibrates in the fetal circulation. To test this, metformin was administered to the pregnant ewe via continuous intravenous infusion or supplementation in the drinking water. Both administration routes increased maternal metformin concentrations to human dose-equivalent concentrations of ~ 10 µM, yet metformin was negligible in the fetus even after 3-4 days of maternal administration. In cotyledon and caruncle tissue, expression levels of the major metformin uptake transporter organic cation transporter 1 (OCT1) were < 1% of expression levels in the fetal liver, a tissue with abundant expression. Expression of other putative uptake transporters OCT2 and OCT3, and efflux transporters multidrug and toxin extrusion (MATE)1 and MATE2were more abundant. These results demonstrate that the ovine placenta is impermeable to maternal metformin administration. This is likely due to anatomical differences and increased interhaemal distance between the maternal and umbilical circulations in the ovine versus human placenta limiting placental metformin transport.
摘要：
在人类怀孕期间，给予母亲的二甲双胍穿过胎盘，导致二甲双胍暴露于胎儿。然而,二甲双胍暴露对胎儿的影响知之甚少，也很难在人类中研究。怀孕绵羊是研究胎儿生理学的强大的大型动物模型。这项研究的目的是确定在人类剂量等效浓度下母体给药的二甲双胍是否穿过绵羊胎盘并在胎儿循环中平衡。为了测试这个，妊娠母羊通过连续静脉输注或在饮用水中补充二甲双胍给药。两种给药途径都将母体二甲双胍浓度增加到约10µM的人体剂量当量浓度，然而,即使在母体给药3~4天后,二甲双胍在胎儿中的表达也可以忽略不计.在子叶和肉梗组织中，主要二甲双胍摄取转运体有机阳离子转运体1（OCT1）的表达水平<胎儿肝脏中表达水平的1％，具有丰富表达的组织。其他假定的摄取转运蛋白OCT2和OCT3以及外排转运蛋白多药和毒素挤出（MATE）1和MATE2的表达更为丰富。这些结果证明绵羊胎盘对于母体二甲双胍给药是不可渗透的。这可能是由于绵羊与人胎盘中母体和脐带循环之间的解剖学差异和血液间距离增加限制了胎盘二甲双胍的转运。
