Absence of Metformin in Fetal Circulation Following Maternal Administration in Late Gestation Pregnant Sheep.
Absence of Metformin in Fetal Circulation Following Maternal Administration in Late Gestation Pregnant Sheep.
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妊娠晚期孕羊母体给药后胎儿循环中缺乏二甲双胍。
DOI：
10.1007/s43032-024-01547-2
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Wesolowski,StephanieR
中科院分区：
文献类型：
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作者：
Rozance,PaulJ;Brown,LauraD;Wesolowski,StephanieR
在人类怀孕期间，给母亲注射二甲双胍会穿过胎盘，导致二甲双胍暴露在胎儿体内。然而，人们对二甲双胍对胎儿的影响知之甚少，也很难在人类身上进行研究。怀孕绵羊是研究胎儿生理学的强有力的大型动物模型。这项研究的目的是确定母体给予人体剂量当量浓度的二甲双胍是否通过绵羊胎盘并在胎儿循环中保持平衡。为了验证这一点，研究人员通过持续静脉输液或在饮用水中补充二甲双胍，对怀孕母羊进行了注射。这两种给药途径都将母亲的二甲双胍浓度增加到人体剂量当量浓度的 ~ 10微米，但即使在母亲给药3-4天后，二甲双胍在胎儿中的浓度也可以忽略不计。在子叶和肉梗组织中，主要的二甲双胍摄取转运体有机阳离子转运体1(OCT1)的表达水平为 <； ，是表达丰富的胎肝组织表达水平的1%。其他可能的摄取转运蛋白OCT2和OCT3，以及外排转运蛋白多药和毒素排出(Mate)1和MATE2的表达更为丰富。这些结果表明，绵羊胎盘对母体给药二甲双胍是不透皮的。这可能是由于绵羊和人类胎盘的母体和脐带循环之间的解剖学差异和血液间距离的增加限制了胎盘二甲双胍的运输。
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 transportersOCT2andOCT3, and efflux transporters multidrug and toxin extrusion (MATE)1andMATE2were 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.