Faculty of Medicine, University of Southampton, UK; Institute for Life Sciences, University of Southampton, UK.
Faculty of Engineering and Physical Sciences, University of Southampton, UK; Institute for Life Sciences, University of Southampton, UK.
J Pharm Sci. 2023 Sep;112(9):2570-2580. doi: 10.1016/j.xphs.2023.05.008. Epub 2023 May 19.
Metformin is an antidiabetic drug, increasingly prescribed in pregnancy and has been shown to cross the human placenta. The mechanisms underlying placental metformin transfer remain unclear. This study investigated the roles of drug transporters and paracellular diffusion in the bidirectional transfer of metformin across the human placental syncytiotrophoblast using placental perfusion experiments and computational modelling. C-metformin transfer was observed in the maternal to fetal and fetal to maternal directions and was not competitively inhibited by 5 mM unlabelled metformin. Computational modelling of the data was consistent with overall placental transfer via paracellular diffusion. Interestingly, the model also predicted a transient peak in fetal C-metformin release due to trans-stimulation of OCT3 by unlabelled metformin at the basal membrane. To test this hypothesis a second experiment was designed. OCT3 substrates (5 mM metformin, 5 mM verapamil and 10 mM decynium-22) added to the fetal artery trans-stimulated release of C-metformin from the placenta into the fetal circulation, while 5 mM corticosterone did not. This study demonstrated activity of OCT3 transporters on the basal membrane of the human syncytiotrophoblast. However, we did not detect a contribution of either OCT3 or apical membrane transporters to overall materno-fetal transfer, which could be represented adequately by paracellular diffusion in our system.
二甲双胍是一种抗糖尿病药物，在妊娠期间越来越多地被开处方，并且已被证明可以穿过胎盘。胎盘二甲双胍转运的机制仍不清楚。本研究使用胎盘灌注实验和计算模型，研究了药物转运体和细胞旁扩散在二甲双胍双向跨胎盘合体滋养层转运中的作用。在母体到胎儿和胎儿到母体的方向上都观察到了 C-二甲双胍的转移，并且未被 5mM 未标记的二甲双胍竞争性抑制。对数据的计算模型与通过细胞旁扩散的整体胎盘转运一致。有趣的是，该模型还预测由于未标记的二甲双胍在基底膜处对 OCT3 的跨刺激，胎儿 C-二甲双胍释放会出现短暂的峰值。为了验证这一假设，设计了第二个实验。OCT3 底物（5mM 二甲双胍、5mM 维拉帕米和 10mM 去氧胆酸）添加到胎儿动脉中，会刺激胎盘向胎儿循环中释放 C-二甲双胍，而 5mM 皮质酮则不会。本研究证明了 OCT3 转运体在人合体滋养层基底膜上的活性。然而，我们没有检测到 OCT3 或顶端膜转运体对整体母胎转移的贡献，在我们的系统中，细胞旁扩散可以充分代表。
