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The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c
Abstract
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, p = 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.
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Metadata
- Authors
- Christensen, M. M. H., Brasch-Andersen, C., Green, H., Nielsen, F., Damkier, P., Beck-Nielsen, H., & Brosen, K.
- Venue
- Pharmacogenetics and Genomics
- Published
- 2011-12
- Volume
- 21
- Issue
- 12
- Pages
- 837-850
- ISSN
- 1744-6872 (ISSN-L)
- OpenAlex
- W1996510156
- Cited by
- 259
- References
- 43
- FWCI
- 15.77
- Type
- journal article
- Language
- en
- Open access
- closed
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