Effect of genetic variation in the organic cation... : Pharmacogenetics and Genomics (original) (raw)

ORIGINAL ARTICLES

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

Chen, Yinga; Li, Shuangliana; Brown, Chalinea; Cheatham, Stephena; Castro, Richard A.a; Leabman, Maya K.a; Urban, Thomas J.a; Chen, Ligonga; Yee, Sook Waha; Choi, Ji Haa; Huang, Yonga; Brett, Claire M.b; Burchard, Esteban G.a; Giacomini, Kathleen M.a

Departments of aBioengineering and Therapeutic Sciences

bAnesthesiology, University of California, San Francisco, California, USA

Correspondence to Professor Kathleen M. Giacomini, PhD, Department of Biopharmaceutical Sciences, University of California, 1550 4th Street, San Francisco, CA 94158, USA

Tel: +1 415 476 1936; fax: +1 415 502 4322; e-mail: [email protected]

Received 3 October 2008 Accepted 10 April 2009

Abstract

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.