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

Ying Chen, Shuanglian Li, Chaline Brown, Stephen Cheatham, Richard A. Castro, Maya K. Leabman, Thomas J. Urban, Ligong Chen, Sook Wah Yee, Ji Ha Choi, Yong Huang, Claire M. Brett, Esteban G. Burchard, Kathleen M. Giacomini

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208 Scopus citations


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 (CLR) and the net secretion (SrCLR) 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 CLR and SrCLR of metformin (P<0.01). CONCLUSION: We conclude that genetic variation in OCT2 plays an important role in the CLR and SrCLR of metformin in healthy volunteers.

Original languageEnglish
Pages (from-to)497-504
Number of pages8
JournalPharmacogenetics and Genomics
Issue number7
StatePublished - 1 Jul 2009


  • Membrane transporter
  • Metformin
  • Organic cation transporter
  • Pharmacogenetics
  • Pharmacokinetics
  • Single nucleotide polymorphism


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