A gene-gene interaction between polymorphisms in the OCT2 and MATE1 genes influences the renal clearance of metformin

Pharmacogenet Genomics. 2013 Oct;23(10):526-34. doi: 10.1097/FPC.0b013e328364a57d.

Abstract

Objective: The aim of this study was to determine the association between the renal clearance (CL(renal)) of metformin in healthy Caucasian volunteers and the single-nucleotide polymorphism (SNP) c.808G>T (rs316019) in OCT2 as well as the relevance of the gene-gene interactions between this SNP and (a) the promoter SNP g.-66T>C (rs2252281) in MATE1 and (b) the OCT1 reduced-function diplotypes.

Methods: Fifty healthy volunteers genotyped for the c.808G>T were enrolled in the study. The distribution was 25 GG, 20 GT, and 5 TT volunteers. The pharmacokinetics of a 500 mg single oral dose of metformin was studied.

Results: When analyzed alone, the c.808 (G>T) affected neither the CL(renal) nor the secretory clearance (CL(sec)) of metformin. However, both CL(renal) and CL(sec) were increased for the volunteers with minor alleles in c.808 (G>T) who were also homozygous for the reference variant g.-66T>C: CL(renal): GG, GT, and TT: 28.1, 34.5, and 44.8 l/h (P = 0.004), respectively and CL(sec): GG, GT, and TT: 21.4, 27.8, and 37.6 l/h (P = 0.005), respectively. In the volunteers with minor alleles in c.808 (G>T) who were also heterozygous for g.-66T>C, both CL(renal) and CL(sec) were found to be reduced (P < 0.028) when compared with volunteers with minor alleles in c.808 (G>T) carrying the g.-66T>C reference genotype.

Conclusion: We report counteracting effects of the c.808 (G>T) and g.-66T>C on the renal elimination of metformin. When adjusted for the genetic variation g.-66T>C, our results suggest that c.808 (G>T) could have a dominant genotype to phenotype correlation.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cohort Studies
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Variation
  • Genotype
  • Healthy Volunteers
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / urine
  • Kidney / drug effects
  • Kidney / metabolism*
  • Linkage Disequilibrium
  • Male
  • Metformin / administration & dosage
  • Metformin / pharmacokinetics*
  • Metformin / urine
  • Organic Cation Transport Proteins / genetics*
  • Organic Cation Transporter 2
  • Polymorphism, Single Nucleotide

Substances

  • Hypoglycemic Agents
  • MATE1 protein, human
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • SLC22A2 protein, human
  • Metformin