Journal of Pharmacokinetics and Pharmacodynamics

, Volume 42, Issue 5, pp 463–475 | Cite as

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

  • Sook Wah Yee
  • Lawrence Lin
  • Matthew Merski
  • Michael J. Keiser
  • Aakash Gupta
  • Youcai Zhang
  • Huan-Chieh Chien
  • Brian K. Shoichet
  • Kathleen M. Giacomini
Original Paper


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.


Organic cation transporter Histamine Serotonin Putrescine Diamine oxidase Metformin 



This project was supported by NIH Grant U19-GM61390 (SWY, KMG), GM71896 (BKS), NIH training grant T32 GM007175 (LL), the Li Ka Shing Foundation (KMG, BKS), the Burroughs Wellcome Fund Innovation in Regulatory Science Awards (Grant BWF ID 1012485) (KMG, BKS), R44GM093456 (MJK), and a Glenn Foundation Award for Research in Biological Mechanisms of Aging (MJK).

Supplementary material

10928_2015_9436_MOESM1_ESM.docx (156 kb)
Supplementary material 1 (DOCX 155 kb)


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Sook Wah Yee
    • 1
  • Lawrence Lin
    • 1
  • Matthew Merski
    • 2
    • 4
  • Michael J. Keiser
    • 1
    • 2
    • 3
  • Aakash Gupta
    • 1
  • Youcai Zhang
    • 1
  • Huan-Chieh Chien
    • 1
  • Brian K. Shoichet
    • 2
  • Kathleen M. Giacomini
    • 1
  1. 1.Department of Bioengineering and Therapeutic SciencesUniversity of California San FranciscoSan FranciscoUSA
  2. 2.Department of Pharmaceutical ChemistryUniversity of California San FranciscoSan FranciscoUSA
  3. 3.Institute for Neurodegenerative DiseasesUniversity of California San FranciscoSan FranciscoUSA
  4. 4.Instituto de Biologia Molecular e CelularUniversidade do PortoPortoPortugal

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