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

Title
Functional characterization of MATE2-K genetic variants and their effects on metformin pharmacokinetics
Authors
Chung J.Y.Cho S.K.Kim T.H.Kim K.H.Jang G.H.Kim C.O.Park E.M.Cho J.Y.Jang I.J.Choi J.H.
Ewha Authors
박은미최지하
SCOPUS Author ID
박은미scopus; 최지하scopus
Issue Date
2013
Journal Title
Pharmacogenetics and Genomics
ISSN
1744-6872JCR Link
Citation
vol. 23, no. 7, pp. 365 - 373
Indexed
SCI; SCIE; SCOPUS WOS scopus
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. © Lippincott Williams & Wilkins.
DOI
10.1097/FPC.0b013e3283622037
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의과대학 > 의학과 > Journal papers
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