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Prediction and validation of enzyme and transporter off-targets for metformin.
Yee, Sook Wah; Lin, Lawrence; Merski, Matthew; Keiser, Michael J; Gupta, Aakash; Zhang, Youcai; Chien, Huan-Chieh; Shoichet, Brian K; Giacomini, Kathleen M.
Afiliação
  • Yee SW; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, 94158-2911, USA.
  • Lin L; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, 94158-2911, USA.
  • Merski M; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, 94158-2550, USA.
  • Keiser MJ; Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150- 180, Porto, Portugal.
  • Gupta A; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, 94158-2911, USA.
  • Zhang Y; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, 94158-2550, USA.
  • Chien HC; Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, 94143, USA.
  • Shoichet BK; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, 94158-2911, USA.
  • Giacomini KM; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, 94158-2911, USA.
J Pharmacokinet Pharmacodyn ; 42(5): 463-75, 2015 Oct.
Article em En | MEDLINE | ID: mdl-26335661
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Membrana Transportadoras / Metformina Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Membrana Transportadoras / Metformina Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article