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

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Abstract

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.

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Acknowledgments

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).

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  1. Matthew Merski

    Present address: Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150- 180, Porto, Portugal

Authors and Affiliations

  1. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, 94158-2911, USA

    Sook Wah Yee, Lawrence Lin, Michael J. Keiser, Aakash Gupta, Youcai Zhang, Huan-Chieh Chien & Kathleen M. Giacomini

  2. Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, 94158-2550, USA

    Matthew Merski, Michael J. Keiser & Brian K. Shoichet

  3. Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, 94143, USA

    Michael J. Keiser

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Correspondence to Kathleen M. Giacomini.

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Sook Wah Yee and Lawrence Lin contributed equally to this work.

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Yee, S.W., Lin, L., Merski, M. et al. Prediction and validation of enzyme and transporter off-targets for metformin. J Pharmacokinet Pharmacodyn 42, 463–475 (2015). https://doi.org/10.1007/s10928-015-9436-y

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  • DOI: https://doi.org/10.1007/s10928-015-9436-y

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