Institute of Clinical Pharmacology, University Medical Center, Georg-August University, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
Int J Mol Sci. 2022 Jul 29;23(15):8430. doi: 10.3390/ijms23158430.
Many organic cations (OCs) may be transported through membranes by a genetically still uncharacterized proton-organic cation (H + OC) antiporter. Here, we characterized an extended substrate spectrum of this antiporter. We studied the uptake of 72 drugs in hCMEC/D3 cells as a model of the human blood-brain barrier. All 72 drugs were tested with exchange transport assays and the transport of 26 of the drugs was studied in more detail concerning concentration-dependent uptake and susceptibility to specific inhibitors. According to exchange transport assays, 37 (51%) drugs were good substrates of the H + OC antiporter. From 26 drugs characterized in more detail, 23 were consistently identified as substrates of the H + OC antiporter in six different assays and transport kinetic constants could be identified with intrinsic clearances between 0.2 (ephedrine) and 201 (imipramine) mL × minute × g protein. Excellent substrates of the H + OC antiporter were no substrates of organic cation transporter OCT1 and vice versa. Good substrates of the H + OC antiporter were more hydrophobic and had a lower topological polar surface area than non-substrates or OCT1 substrates. These data and further research on the H + OC antiporter may result in a better understanding of pharmacokinetics, drug-drug interactions and variations in pharmacokinetics.
许多有机阳离子（OCs）可能通过一种尚未被基因鉴定的质子-有机阳离子（H + OC）反向转运体通过膜转运。在这里，我们描述了该反向转运体的扩展底物谱。我们研究了 72 种药物在 hCMEC/D3 细胞中的摄取，作为人血脑屏障的模型。所有 72 种药物均通过交换转运测定进行了测试，其中 26 种药物的摄取进行了更详细的研究，包括浓度依赖性摄取和对特定抑制剂的敏感性。根据交换转运测定，37 种（51％）药物是 H + OC 反向转运体的良好底物。在更详细地描述的 26 种药物中，有 23 种在六种不同的测定中被一致鉴定为 H + OC 反向转运体的底物，并且可以确定转运动力学常数，内在清除率在 0.2（麻黄碱）和 201（丙咪嗪）mL×分钟×g 蛋白之间。H + OC 反向转运体的良好底物不是有机阳离子转运蛋白 OCT1 的底物，反之亦然。H + OC 反向转运体的良好底物比非底物或 OCT1 底物具有更高的疏水性和更低的拓扑极性表面积。这些数据以及对 H + OC 反向转运体的进一步研究可能会更好地理解药代动力学，药物相互作用和药代动力学的变化。
