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The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c
KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
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2011 (English)In: Pharmacogenetics & Genomics, ISSN 1744-6872, Vol. 21, no 12, 837-850 p.Article in journal (Refereed) Published
Abstract [en]

Objective The aim of this study was to evaluate the effect of genetic variations in OCT1, OCT2, MATE1, MATE 2, and PMAT on the trough steady-state plasma concentration of metformin and hemoglobin A1c (Hb1Ac). Method The South Danish Diabetes Study was a 2 x 2 x 2 factorial, prospective, randomized, double-blind, placebo-controlled, multicentre study. One hundred and fifty-nine patients received 1 g of metformin, twice daily continuously, and 415 repeated plasma metformin measurements were obtained after 3, 6, and 9 months of treatment.

Results The mean trough steady-state metformin plasma concentration was estimated to be 576 ng/ml (range, 54-4133 ng/ml, rho = 0.55) and correlated to the number of reduced function alleles in OCT1 (none, one or two: 642, 542, 397 ng/ml; P = 0.001). The absolute decrease in Hb1Ac both initially and long term was also correlated to the number of reduced function alleles in OCT1 resulting in diminished pharmacodynamic effect of metformin after 6 and 24 months.

Conclusion In a large cohort of type 2 diabetics, we either confirm or show for the first time: (a) an enormous 80-fold) variability in trough steady-state metformin plasma concentration, (b) OCT1 activity affects metformin steady-state pharmacokinetics, and (c) OCT1 genotype has a bearing on HbA1c during metformin treatment.

Place, publisher, year, edition, pages
2011. Vol. 21, no 12, 837-850 p.
Keyword [en]
MATE1, MATE2, metformin, OCT1, OCT2, personalized medicine, pharmacogenetics, PMAT, steady state, type 2 diabetes
National Category
Biological Sciences
URN: urn:nbn:se:kth:diva-50867DOI: 10.1097/FPC.0b013e32834c0010ISI: 000296799900008OAI: diva2:468859
QC 20111221Available from: 2011-12-21 Created: 2011-12-08 Last updated: 2012-01-09Bibliographically approved

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Green, Henrik
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