Effects of tetraalkylammonium compounds with different affinities for organic cation transporters on the pharmacokinetics of metformin

Biopharm Drug Dispos. 2007 Dec;28(9):501-10. doi: 10.1002/bdd.576.


The study sought to investigate the effects of tetraalkylammonium (TAA), inhibitors of the organic cation transporters (OCTs) with different affinities, on the pharmacokinetics of metformin. The inhibitory potentials of TAAs on the uptake of metformin were evaluated by determining IC(50) values in MDCK cells over-expressing OCTs and, to assess in vivo drug interactions, metformin and TAAs were coadministered to rats. Uptake of metformin was facilitated by over-expression of hOCT1 and hOCT2 and showed saturable processes, indicating that metformin is a substrate of hOCT1 and hOCT2. The IC(50) values of TAAs for hOCT2 were lower than hOCT1 and decreased with increasing alkyl chain length, indicating that the inhibitory potential of TAAs on metformin uptake was greater in hOCT2 than in hOCT1 and increased with increasing alkyl chain length. The plasma concentration of metformin was elevated by the coadministration of tetrapropylammonium (TPrA) and tetrapentylammonium (TPeA), but not by tetramethylammonium (TMA) or tetraethylammonium (TEA). However, the plasma concentrations of TMA, TEA and TPrA were not changed by the coadministration of metformin. In conclusion, in vivo drug interactions between metformin and TAAs were caused only when metformin was coadministered with TAAs showing higher affinities for OCTs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Dogs
  • Drug Interactions
  • Gene Expression Regulation
  • Humans
  • Hypoglycemic Agents / pharmacokinetics*
  • Inhibitory Concentration 50
  • Male
  • Metformin / pharmacokinetics*
  • Organic Cation Transport Proteins / drug effects*
  • Organic Cation Transport Proteins / genetics
  • Organic Cation Transport Proteins / metabolism
  • Organic Cation Transporter 1 / drug effects
  • Organic Cation Transporter 1 / genetics
  • Organic Cation Transporter 1 / metabolism
  • Organic Cation Transporter 2
  • Quaternary Ammonium Compounds / chemistry
  • Quaternary Ammonium Compounds / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship


  • Hypoglycemic Agents
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 1
  • Organic Cation Transporter 2
  • Quaternary Ammonium Compounds
  • SLC22A2 protein, human
  • Metformin