title: A gene-gene interaction between polymorphisms in the OCT2 and MATE1 genes influences the renal clearance of metformin.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: aInstitute of Public Health, Clinical Pharmacology, University of Southern Denmark bDepartment of Clinical Genetics cDepartment of Clinical Chemistry and Pharmacology dDepartment of Endocrinology, Odense University Hospital, Odense, Denmark.
authors.forename: Mette M H
authors.initials: MM
authors.lastname: Christensen
authors.forename: Rasmus S
authors.initials: RS
authors.lastname: Pedersen
authors.forename: Tore B
authors.initials: TB
authors.lastname: Stage
authors.forename: Charlotte
authors.initials: C
authors.lastname: Brasch-Andersen
authors.forename: Flemming
authors.initials: F
authors.lastname: Nielsen
authors.forename: Per
authors.initials: P
authors.lastname: Damkier
authors.forename: Henning
authors.initials: H
authors.lastname: Beck-Nielsen
authors.forename: Kim
authors.initials: K
authors.lastname: Brøsen
mesh_terms: D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D015810:Linkage Disequilibrium; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D000075102:Organic Cation Transporter 2; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; D008687:Metformin