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

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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.