title: 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).
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors: Institute of Public Health, Clinical Pharmacology, University of Southern Denmark, Odense, Denmark. mmchristensen@health.sdu.dk
authors: Mette M H
authors: MM
authors: Christensen
authors: Charlotte
authors: C
authors: Brasch-Andersen
authors: Henrik
authors: H
authors: Green
authors: Flemming
authors: F
authors: Nielsen
authors: Per
authors: P
authors: Damkier
authors: Henning
authors: H
authors: Beck-Nielsen
authors: Kim
authors: K
authors: Brosen
mesh_terms: D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood*; D008687:Metformin / Q000008:administration & dosage / Q000097:blood*; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D027701:Organic Cation Transport Proteins / Q000235:genetics; D027702:Organic Cation Transporter 1 / Q000235:genetics; D000075102:Organic Cation Transporter 2; D011446:Prospective Studies
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human