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

Pharmacogenomics J. 2011 Dec;11(6):400-11. doi: 10.1038/tpj.2010.54. Epub 2010 Jun 22.


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 (14)C-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 IC(50) values up to 23 times lower than those of the OCT1-reference. Uptake studies using (14)C-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Drug Interactions
  • Genotype*
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Inhibitory Concentration 50
  • Kinetics
  • Metformin / chemistry
  • Metformin / pharmacology*
  • Methylamines / chemistry
  • Organic Cation Transporter 1 / antagonists & inhibitors*
  • Organic Cation Transporter 1 / metabolism
  • Pyridinium Compounds / chemistry


  • 4-(4-(dimethylamino)styryl)-1-methylpyridinium iodide
  • Hypoglycemic Agents
  • Methylamines
  • Organic Cation Transporter 1
  • Pyridinium Compounds
  • Green Fluorescent Proteins
  • Metformin