Functional characterization of MATE2-K genetic variants and their effects on metformin pharmacokinetics

Jae Yong Chung, Sung Kweon Cho, Tae Hee Kim, Kyoung Hee Kim, Geun Hye Jang, Choon Ok Kim, Eun Mi Park, Joo Youn Cho, In Jin Jang, Ji Ha Choi

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19 Scopus citations

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 ofMATE2-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. Conclusion Our study suggests that common promoter haplotypes of MATE2-K are associated with the pharmacokinetics of metformin.

Original languageEnglish
Pages (from-to)365-373
Number of pages9
JournalPharmacogenetics and Genomics
Volume23
Issue number7
DOIs
StatePublished - 1 Jul 2013

Keywords

  • Genetic Variant
  • Haplotype
  • Mate2-K
  • Metformin
  • Pharmacokinetics
  • Promoter
  • Slc47A2
  • Transcriptional Activity
  • Transporter

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