caa a22 4500 605534152 CHVBK 20210128100841.0 cr unu---uuuuu 210128e20151001xx s 000 0 eng 10.1007/s10928-015-9436-y doi (NATIONALLICENCE)springer-10.1007/s10928-015-9436-y Prediction and validation of enzyme and transporter off-targets for metformin [Elektronische Daten] [Sook Yee, Lawrence Lin, Matthew Merski, Michael Keiser, Aakash Gupta, Youcai Zhang, Huan-Chieh Chien, Brian Shoichet, Kathleen Giacomini] 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=1.5mM). 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±3.1mM. In this study, we found that metformin inhibited intestinal amine transporters and DAO at concentrations that may be achieved intheintestine after therapeutic doses. Further studies are warranted to determine the relevance of these interactions to the adverse effects of metformin on the gastrointestinal tract. Springer Science+Business Media New York, 2015 Organic cation transporter nationallicence Histamine nationallicence Serotonin nationallicence Putrescine nationallicence Diamine oxidase nationallicence Metformin nationallicence Yee Sook Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA aut Lin Lawrence Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA aut Merski Matthew Department of Pharmaceutical Chemistry, University of California San Francisco, 94158-2550, San Francisco, CA, USA aut Keiser Michael Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA aut Gupta Aakash Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA aut Zhang Youcai Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA aut Chien Huan-Chieh Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA aut Shoichet Brian Department of Pharmaceutical Chemistry, University of California San Francisco, 94158-2550, San Francisco, CA, USA aut Giacomini Kathleen Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/5(2015-10-01), 463-475 1567-567X 42:5<463 2015 42 10928 https://doi.org/10.1007/s10928-015-9436-y text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-015-9436-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Yee Sook Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA aut NATIONALLICENCE 700 1- Lin Lawrence Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA aut NATIONALLICENCE 700 1- Merski Matthew Department of Pharmaceutical Chemistry, University of California San Francisco, 94158-2550, San Francisco, CA, USA aut NATIONALLICENCE 700 1- Keiser Michael Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA aut NATIONALLICENCE 700 1- Gupta Aakash Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA aut NATIONALLICENCE 700 1- Zhang Youcai Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA aut NATIONALLICENCE 700 1- Chien Huan-Chieh Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA aut NATIONALLICENCE 700 1- Shoichet Brian Department of Pharmaceutical Chemistry, University of California San Francisco, 94158-2550, San Francisco, CA, USA aut NATIONALLICENCE 700 1- Giacomini Kathleen Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/5(2015-10-01), 463-475 1567-567X 42:5<463 2015 42 10928