Computational Modelling of Paracellular Diffusion and OCT3 Mediated Transport of Metformin in the Perfused Human Placenta
Computational Modelling of Paracellular Diffusion and OCT3 Mediated Transport of Metformin in the Perfused Human Placenta
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DOI：
10.1016/j.xphs.2023.05.008
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发表时间：
2023-08-15
影响因子：
3.8
通讯作者：
Sengers，Bram G.
中科院分区：
文献类型：
--
作者：
Lofthouse，Emma M.;Cleal，Jane;Sengers，Bram G.
二甲双胍是一种抗糖尿病药物，在怀孕期间越来越多地被开出，并已被证明可以穿过人类胎盘。胎盘二甲双胍转移的机制尚不清楚。本研究通过胎盘灌流实验和计算机模拟，研究了药物转运体和细胞旁扩散在二甲双胍通过人胎盘合体滋养层双向转移中的作用。14C-二甲双胍在母体到胎儿和胎儿到母体的方向都观察到了转移，并且不被5 mM未标记的二甲双胍竞争性地抑制。数据的计算模型与胎盘通过细胞旁扩散的整体转移是一致的。有趣的是，该模型还预测了由于未标记的二甲双胍在基底膜上反式刺激Oct3而导致胎儿14C-二甲双胍释放的瞬时峰值。为了验证这一假设，设计了第二个实验。在胎儿动脉中加入Oct3底物(5 mM二甲双胍、5 mM维拉帕米和10 mM地塞米松-22)，反式刺激14C-二甲双胍从胎盘释放到胎儿循环中，而5 mM皮质酮则没有。本研究证实了人合体滋养层细胞基底膜上Oct3转运蛋白的活性。然而，我们没有检测到Oct3或顶膜转运蛋白对整个母胎移植的贡献，这可以通过我们的系统中的细胞旁扩散来充分表示。
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.14C-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 fetal14C-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 of14C-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.