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Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1: predictions of metformin interactions

Abstract

Common genetic variants of the liver-specific human organic cation transporter 1 (OCT1; SLC22A1) have reduced transport capacity for substrates such as the antidiabetic drug metformin. The effect of the reduced OCT1 function on drug interactions associated with OCT1 has not been investigated and was, therefore, the focus of the study presented here. HEK293 cells expressing human OCT1-reference or the variants R61C, V408M, M420del and G465R were first used to study the kinetics and inhibition pattern of the OCT1 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP+). In the second part OCT1-mediated 14C-metformin uptake was studied in the presence of drugs administered concomitantly with metformin. Transport studies using ASP+ showed that the function of the variants decreased in the following order: OCT1-reference=V408M=M420del >R61C >>G465R. Variants M420del and R61C were more sensitive to drug inhibition, with IC50 values up to 23 times lower than those of the OCT1-reference. Uptake studies using 14C-metformin were in qualitative agreement with those using ASP+, with the exception that a larger reduction in transport capacity was observed for M420del. Concomitantly administered drugs, such as verapamil and amitriptyline, revealed potential drug–drug interactions at clinical plasma concentrations of metformin for OCT1-M420del.

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Abbreviations

ASP+:

4-(4-(dimethylamino)styryl)-N-methylpyridinium

DDI:

drug–drug interaction

HSA:

human serum albumin

HEK293:

human embryonic kidney

MPP+:

1-methyl-4-phenylpyridinium

OCT:

organic cation transporter

SLC:

solute carrier

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Acknowledgements

This work was supported by a PhD study grant from AstraZeneca to Gustav Ahlin; the Swedish Research Council (Grant 9478); the Knut and Alice Wallenberg Foundation; the Swedish Fund for Research without Animal Experiments and the Swedish Board of Agriculture.

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Correspondence to P Artursson.

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Ahlin, G., Chen, L., Lazorova, L. et al. Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1: predictions of metformin interactions. Pharmacogenomics J 11, 400–411 (2011). https://doi.org/10.1038/tpj.2010.54

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