Effect of Genetic Variation in the Organic Cation Transporter 2, OCT2, on the Renal Elimination of Metformin

Objective—The goal of this study was to determine the effect of a genetic variant in the organic cation transporter (OCT2), OCT2-808G/T, which results in an amino acid change, A270S, on the pharmacokinetics of the anti-diabetic 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 [fourteen homozygous for the OCT2 reference allele (808G/G) and nine heterozygous for the variant allele (808G/T, *3D)] were recruited into 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 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 were characterized in twenty-three healthy volunteers of Caucasian and African American ancestries. We observed that the renal clearance (CLR) and the net secretion (SrCLR) of metformin wer