Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin

Pharmacogenet Genomics. 2009 Jul;19(7):497-504. doi: 10.1097/FPC.0b013e32832cc7e9.


Objective: The goal of this study was to determine the effect of a genetic variant in the organic cation transporter 2 (OCT2), OCT2-808G/T, which results in an amino acid change, A270S, on the pharmacokinetics of the antidiabetic drug, metformin.

Methods: The uptake of metformin was performed in stably transfected HEK-293 cells expressing the empty vector (MOCK), the reference OCT2-808G, and the variant OCT2-808T. Healthy individuals with known OCT2 genotypes [14 homozygous for the OCT2 reference allele (808G/G) and nine heterozygous for the variant allele (808G/T, *3D)] were recruited to this study. Metformin concentrations in plasma and urine were measured by liquid chromatography-tandem mass spectrometry method. Creatinine levels were also measured in plasma and urine. Pharmacokinetic parameters were evaluated for both the groups.

Results: We observed that in HEK-293 stably transfected cells, OCT2-808T had a greater capacity to transport metformin than did the reference OCT2. Metformin pharmacokinetics was characterized in 23 healthy volunteers of Caucasian and African-American ancestries. We observed that the renal clearance (CL(R)) and the net secretion (SrCL(R)) of metformin were significantly different between the volunteers heterozygous for the variant allele (808G/T), and the volunteers homozygous for the reference allele (808G/G) (P<0.005). Multivariate analysis revealed that OCT2 genotype was a significant predictor of CL(R) and SrCL(R) of metformin (P<0.01).

Conclusion: We conclude that genetic variation in OCT2 plays an important role in the CL(R) and SrCL(R) of metformin in healthy volunteers.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Biological Transport
  • Cell Line
  • Genetic Linkage
  • Homozygote
  • Humans
  • Kidney / metabolism*
  • Metformin / blood
  • Metformin / pharmacokinetics*
  • Metformin / urine
  • Mutant Proteins / genetics
  • Organic Cation Transport Proteins / genetics*
  • Organic Cation Transport Proteins / metabolism*
  • Organic Cation Transporter 2
  • Polymorphism, Single Nucleotide / genetics*
  • Time Factors


  • Mutant Proteins
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • SLC22A2 protein, human
  • Metformin