Effects of genetic polymorphisms in the organic cation transporter OCT1 on cellular uptake and metabolism of antidepressants and other drugs

抗抑郁药物的疗效和副作用在不同患者之间差别很大。文献资料和自己的初步数据表明，有机阳离子转运体OCT1可能介导肝细胞对许多抗抑郁药的摄取。因此，我们假设OCT1的遗传多态性和OCT1的药物相互作用可能影响肝细胞摄取，进而影响许多抗抑郁药的生物转化、药代动力学和临床效果。首先，我们计划在体外分析oct1介导的抗抑郁药物的细胞摄取。在这里，我们将使用过表达OCT1和OCT1变体的重组细胞系分析OCT1遗传多态性和药物-药物相互作用对OCT1的影响。其次，我们计划在具有代表性的OCT1和CYP2D6基因型活跃和缺陷的健康人类志愿者中使用抗抑郁药阿米替林、西酞普兰和帕罗西汀进行研究。第三，我们将分析顺位和反位遗传多态性对OCT1转录调控的影响。OCT1多态性和该转运体上的药物相互作用的影响可能有助于未来单独优化药物治疗。迄今为止，OCT1和CYP2D6之间的基因-基因相互作用尚未得到研究，但可能具有广泛的医学和科学影响。该项目的数据可能有助于理解OCT1在肝细胞对阳离子药物摄取中的作用，包括其化学结构与抑制和运输电位之间的关系。最后，这些分析应该有助于理解OCT1的转录调控。

Efficacy and side-effects of antidepressive drugs are highly variable between patients. Literature data and preliminary own data suggest that the organic cation transporter OCT1 may mediate liver cell uptake of many antidepressants. Therefore, we hypothesize that genetic polymorphisms in OCT1 and dug-drug interactions at OCT1 may affect liver cell uptake, and consecutively biotransformation, pharmacokinetics and clinical effects of many antidepressants. First, we plan in vitro analyses of the OCT1-mediated cellular uptake of antidepressants. Here we will analyze effects of OCT1 genetic polymorphisms and drug-drug interactions at OCT1 using recombinant cell lines overexpressing OCT1 and OCT1 variants. Second, we plan studies with the antidepressants amitriptyline, citalopram and paroxetine in healthy human volunteers with representative active and deficient genotypes of OCT1 and CYP2D6. Third, we will analyze effects of cis- and trans located genetic polymorphisms on transcriptional regulation of OCT1. The effects of OCT1 polymorphisms and drug interactions at this transporter may contribute to individually optimized drug therapies in future. Gene-gene interactions between OCT1 and CYP2D6 have thus far not been studied but may have a broad medical and scientific impact. Data from this project may contribute to understanding of the role of OCT1 in hepatocellular uptake of cationic drugs, including the relationships between the chemical structure and inhibitory and transport potential. Finally the analyses should contribute to the understanding of OCT1 transcriptional regulation.