Articles
Clinical Pharmacology & Therapeutics (2009); 86 3, 299–306. doi:10.1038/clpt.2009.92
There is a Commentary (December 2009) associated with this Article.
The Effects of Genetic Polymorphisms in the Organic Cation Transporters OCT1, OCT2, and OCT3 on the Renal Clearance of Metformin
M V Tzvetkov1, S V Vormfelde1, D Balen2, I Meineke1, T Schmidt1, D Sehrt1, I Saboli
2, H Koepsell3 and J Brockmöller1
- 1Department of Clinical Pharmacology, University Medical Center, University of Göttingen, Göttingen, Germany
- 2Institute for Medical Research and Occupational Health, Zagreb, Croatia
- 3Institute of Anatomy and Cell Biology, Julius Maximilians University Würzburg, Würzburg, Germany
Correspondence: J Brockmöller, (jbrockm@gwdg.de)
Received 18 February 2009; Accepted 21 April 2009; Published online 17 June 2009.
Abstract
Organic cation transporters (OCTs) can mediate metformin transmembrane transport. We explored metformin pharmacokinetics in relation to genetic variations in OCT1, OCT2, OCT3, OCTN1, and MATE1 in 103 healthy male Caucasians. Renal clearance varied 3.8-fold and was significantly dependent on creatinine clearance (r2 = 0.42, P < 0.0001), age (r2 = 0.09, P = 0.002), and OCT1 polymorphisms. Carriers of zero, one, and two low-activity OCT1 alleles (Arg61Cys, Gly401Ser, 420del, or Gly465Arg) had mean renal clearances of 30.6, 33.1, and 37.1 l/h, respectively (P = 0.04, after adjustment for creatinine clearance and age). Immunohistochemical staining of human kidneys demonstrated OCT1 expression on the apical side of proximal and distal tubules. Increased renal clearance, in parallel with the known decreased hepatic uptake, may contribute to reduced metformin efficacy in low-activity genotypes. Renal OCT1 expression may be important not only in relation to metformin but with respect to other drugs as well.
