title: Functional characterization of MATE2-K genetic variants and their effects on metformin pharmacokinetics.
abstract: OBJECTIVE
  Human multidrug and toxin extrusion member 2 (MATE2-K, SLC47A2) plays an important role in the renal elimination of various clinical drugs including the antidiabetic drug metformin. The goal of this study was to characterize genetic variants of MATE2-K and determine their association with the pharmacokinetics of metformin.
  
  
  METHODS
  We screened DNA samples from 48 healthy Koreans for variants in the promoter and coding regions of MATE2-K and examined the function of common haplotypes in the promoter region using in-vitro luciferase assays. Then, the metformin pharmacokinetic study was carried out to determine the association between MATE2-K promoter haplotypes and metformin pharmacokinetics.
  
  
  RESULTS
  Nine variants in the promoter region of MATE2-K and one nonsynonymous variant, p.G211V, were identified. The MATE2-K promoter haplotype 1 containing a known functional polymorphism, g.-130G>A and haplotype 2 containing two polymorphisms, g.-609G>A and g.-396G>A showed a significant increase in reporter activity. Among the 45 individuals who participated in the metformin pharmacokinetic study, 12 healthy Koreans who were homozygous for haplotype 1 or 2 showed a significant increase in renal clearance [539 ± 76 (reference group) vs. 633 ± 102 (variant group) ml/min; P=0.006] and secretion clearance [439 ± 81 (reference group) vs. 531 ± 102 (variant group) ml/min; P=0.007] of metformin compared with that shown by the reference group.
  
  
  CONCLUSIONS
  Our study suggests that common promoter haplotypes of MATE2-K are associated with the pharmacokinetics of metformin.
authors: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea.
authors: Jae-Yong
authors: JY
authors: Chung
authors: Sung Kweon
authors: SK
authors: Cho
authors: Tae Hee
authors: TH
authors: Kim
authors: Kyoung Hee
authors: KH
authors: Kim
authors: Geun Hye
authors: GH
authors: Jang
authors: Choon Ok
authors: CO
authors: Kim
authors: Eun-Mi
authors: EM
authors: Park
authors: Joo-Youn
authors: JY
authors: Cho
authors: In-Jin
authors: IJ
authors: Jang
authors: Ji Ha
authors: JH
authors: Choi
mesh_terms: D044466:Asian People; D014644:Genetic Variation; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008687:Metformin / Q000493:pharmacokinetics*; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic
chemical_list: D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; C521870:SLC47A2 protein, human; D008687:Metformin