Prediction and validation of enzyme and transporter off-targets for metformin

J Pharmacokinet Pharmacodyn. 2015 Oct;42(5):463-75. doi: 10.1007/s10928-015-9436-y. Epub 2015 Sep 3.


Metformin, an established first-line treatment for patients with type 2 diabetes, has been associated with gastrointestinal (GI) adverse effects that limit its use. Histamine and serotonin have potent effects on the GI tract. The effects of metformin on histamine and serotonin uptake were evaluated in cell lines overexpressing several amine transporters (OCT1, OCT3 and SERT). Metformin inhibited histamine and serotonin uptake by OCT1, OCT3 and SERT in a dose-dependent manner, with OCT1-mediated amine uptake being most potently inhibited (IC50 = 1.5 mM). A chemoinformatics-based method known as Similarity Ensemble Approach predicted diamine oxidase (DAO) as an additional intestinal target of metformin, with an E-value of 7.4 × 10(-5). Inhibition of DAO was experimentally validated using a spectrophotometric assay with putrescine as the substrate. The Ki of metformin for DAO was measured to be 8.6 ± 3.1 mM. In this study, we found that metformin inhibited intestinal amine transporters and DAO at concentrations that may be achieved in the intestine after therapeutic doses. Further studies are warranted to determine the relevance of these interactions to the adverse effects of metformin on the gastrointestinal tract.

Keywords: Diamine oxidase; Histamine; Metformin; Organic cation transporter; Putrescine; Serotonin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amine Oxidase (Copper-Containing) / metabolism
  • Biological Transport / physiology
  • Cell Line
  • Diabetes Mellitus, Type 2 / metabolism
  • HEK293 Cells
  • Humans
  • Intestinal Mucosa / metabolism
  • Kinetics
  • Membrane Transport Proteins / metabolism*
  • Metformin / metabolism*
  • Octamer Transcription Factor-3 / metabolism
  • Organic Cation Transporter 1 / metabolism
  • Serotonin Plasma Membrane Transport Proteins / metabolism


  • Membrane Transport Proteins
  • Octamer Transcription Factor-3
  • Organic Cation Transporter 1
  • POU5F1 protein, human
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Metformin
  • Amine Oxidase (Copper-Containing)