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

有机阳离子转运蛋白OCT1基因多态性对抗抑郁药和其他药物细胞摄取和代谢的影响

基本信息

批准号：
190178361
负责人：
Professor Dr. Mladen Vassilev Tzvetkov
金额：
--
依托单位：
Institut für Klinische Pharmakologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/190178361?language=en
关键词：
Effects genetic polymorphisms organic cation

项目摘要

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.

抗抑郁药物的疗效和副作用在患者之间差异很大。文献数据和初步的自身数据表明，有机阳离子转运蛋白OCT 1可能介导许多抗抑郁药的肝细胞摄取。因此，我们假设OCT 1的遗传多态性和OCT 1的药物相互作用可能会影响肝细胞摄取，并连续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OCT 1介导的抗抑郁药的细胞摄取。在这里，我们将使用过表达OCT 1和OCT 1变体的重组细胞系分析OCT 1遗传多态性和OCT 1处的药物-药物相互作用的影响。其次，我们计划在具有代表性的OCT 1和CYP 2D 6活性和缺陷基因型的健康人类志愿者中进行抗抑郁药阿米替林、西酞普兰和帕罗西汀的研究。第三，我们将分析顺式和反式基因多态性对OCT 1转录调控的影响。OCT 1多态性和药物相互作用在这个转运蛋白的影响可能有助于在未来的个体优化的药物治疗。OCT 1和CYP 2D 6之间的基因-基因相互作用迄今尚未研究，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OCT 1在肝细胞摄取阳离子药物中的作用，包括化学结构与抑制和转运潜力之间的关系。最后，分析应有助于理解OCT 1的转录调控。