Identification of Novel Substrates and Structure-Activity Relationship of Cellular Uptake Mediated by Human Organic Cation Transporters 1 and 2
Identification of Novel Substrates and Structure-Activity Relationship of Cellular Uptake Mediated by Human Organic Cation Transporters 1 and 2
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DOI：
10.1021/jm400966v
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发表时间：
2013-09-26
影响因子：
7.3
通讯作者：
Gustavsson, Lena
中科院分区：
文献类型：
--
作者：
Hendrickx, Ramon;Johansson, Jenny G.;Gustavsson, Lena
最近，人类有机阳离子转运蛋白1(hOCT1/SLC22A1)和2(hOCT2/SLC22A2)在药物处置中的临床重要性已经被强调，例如清除、毒性和药物与药物的相互作用[Annu。法玛科牧师。托昔康。2012，52,249-273；NAT。因此，在ADMET(吸收、分布、代谢、排泄、毒性)研究中，广泛需要对结构转运关系的实验评估以及预测这些转运体的药物摄取的工具。在本研究中，我们建立了一种可靠的方法来筛选hOCT1和hOCT2在HEK293细胞中摄取未标记化合物。首次提出了一个包含354种化合物吸收的广泛数据集。正如预期的那样，这两种有机阳离子转运蛋白在底物特异性上有很大的重叠。然而，鉴定了几种被hOCT1或hOCT2选择性摄取的化合物。特别是，一系列苯基噻吩甲酰胺脲被鉴定为选择性hOCT1底物。此外，转运的驱动因素不同：分子体积是hOCT1底物最重要的决定因素，而极性表面积(PSA)等氢键参数对hOCT2起主导作用。
Recently the clinical importance of human organic cation transporters 1 (hOCT1/SLC22A1) and 2 (hOCT2/SLC22A2) in drug disposition, for example, clearance, toxicity, and drug-drug interactions, have been highlighted [Annu. Rev. Pharmacol. Toxicol. 2012, 52, 249-273; Nat. Rev. Drug Discovery 2010, 9 (3), 215-236] Consequently, there is an extensive need for experimental assessment of structure transport relationships as well as tools to predict drug uptake by these transporters in ADMET (absorption, distribution, metabolism, excretion, toxicity) investigations. In the present study, we developed a robust assay for screening unlabeled compound uptake by hOCT1 and hOCT2 using transfected HEK293 cells. For the first time, an extensive data set comprising uptake of 354 compounds is presented. As expected, there was a large overlap in substrate specificity between the two organic cation transporters. However, several compounds selectively taken up by either hOCT1 or hOCT2 were identified. In particular, a chemical series of phenylthiophenecarboxamide ureas was identified as selective hOCT1 substrates. Moreover, the drivers for transport differed: molecular volume was the most important determinant of hOCT1 substrates, whereas H-bonding parameters like polar surface area (PSA) dominated for hOCT2.