Influences of organic cation transporter polymorphisms on the population pharmacokinetics of metformin in healthy subjects

AAPS J. 2013 Apr;15(2):571-80. doi: 10.1208/s12248-013-9460-z. Epub 2013 Feb 16.


This study investigated the effects of genetic polymorphisms in organic cation transporter (OCT) genes, such as OCT1-3, OCTN1, MATE1, and MATE2-K, on metformin pharmacokinetics. Of particular interest was the influence of genetic polymorphisms as covariates on the variability in the population pharmacokinetics (PPK) of metformin using nonlinear mixed effects modeling (NONMEM). In a retrospective data analysis, data on subjects from five independent metformin bioequivalence studies that used the same protocol were assembled and compared with 96 healthy control subjects who were administered a single oral 500 mg dose of metformin. Genetic polymorphisms of OCT2-808 G>T and OCTN1-917C>T had a significant (P<0.05) effect on metformin pharmacokinetics, yielding a higher peak concentration with a larger area under the serum time-concentration curve. The values obtained were 102±34.5 L/h for apparent oral clearance (CL/F), 447±214 L for volume of distribution (V d/F), and 3.1±0.9 h for terminal half-life (mean±SD) by non-compartmental analysis. The NONMEM method gives similar results. The metformin serum levels were obtained by setting the one-compartment model to a first-order absorption and lag time. In the PPK model, the effects of OCT2-808 G>T and OCTN1-917C>T variants on the CL/F were significant (P<0.001 and P<0.05, respectively). Thus, genetic variants of OCTN1-917C>T, along with OCT2-808 G>T genetic polymorphisms, could be useful in titrating the optimal metformin dose.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Analysis of Variance
  • Chi-Square Distribution
  • Drug Dosage Calculations
  • Gene Frequency
  • Genotype
  • Half-Life
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics*
  • Male
  • Metabolic Clearance Rate
  • Metformin / administration & dosage
  • Metformin / blood
  • Metformin / pharmacokinetics*
  • Models, Biological*
  • Nonlinear Dynamics*
  • Organic Cation Transport Proteins / genetics*
  • Organic Cation Transport Proteins / metabolism*
  • Organic Cation Transporter 2
  • Pharmacogenetics
  • Phenotype
  • Polymorphism, Genetic*
  • Randomized Controlled Trials as Topic
  • Retrospective Studies
  • Symporters
  • Young Adult


  • Hypoglycemic Agents
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • SLC22A2 protein, human
  • SLC22A4 protein, human
  • Symporters
  • Metformin