Prediction and validation of enzyme and transporter off-targets for metformin
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| 024 | 7 | 0 | |a 10.1007/s10928-015-9436-y |2 doi |
| 035 | |a (NATIONALLICENCE)springer-10.1007/s10928-015-9436-y | ||
| 245 | 0 | 0 | |a Prediction and validation of enzyme and transporter off-targets for metformin |h [Elektronische Daten] |c [Sook Yee, Lawrence Lin, Matthew Merski, Michael Keiser, Aakash Gupta, Youcai Zhang, Huan-Chieh Chien, Brian Shoichet, Kathleen Giacomini] |
| 520 | 3 | |a 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. | |
| 540 | |a Springer Science+Business Media New York, 2015 | ||
| 690 | 7 | |a Organic cation transporter |2 nationallicence | |
| 690 | 7 | |a Histamine |2 nationallicence | |
| 690 | 7 | |a Serotonin |2 nationallicence | |
| 690 | 7 | |a Putrescine |2 nationallicence | |
| 690 | 7 | |a Diamine oxidase |2 nationallicence | |
| 690 | 7 | |a Metformin |2 nationallicence | |
| 700 | 1 | |a Yee |D Sook |u Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA |4 aut | |
| 700 | 1 | |a Lin |D Lawrence |u Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA |4 aut | |
| 700 | 1 | |a Merski |D Matthew |u Department of Pharmaceutical Chemistry, University of California San Francisco, 94158-2550, San Francisco, CA, USA |4 aut | |
| 700 | 1 | |a Keiser |D Michael |u Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA |4 aut | |
| 700 | 1 | |a Gupta |D Aakash |u Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA |4 aut | |
| 700 | 1 | |a Zhang |D Youcai |u Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA |4 aut | |
| 700 | 1 | |a Chien |D Huan-Chieh |u Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA |4 aut | |
| 700 | 1 | |a Shoichet |D Brian |u Department of Pharmaceutical Chemistry, University of California San Francisco, 94158-2550, San Francisco, CA, USA |4 aut | |
| 700 | 1 | |a Giacomini |D Kathleen |u Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA |4 aut | |
| 773 | 0 | |t Journal of Pharmacokinetics and Pharmacodynamics |d Springer US; http://www.springer-ny.com |g 42/5(2015-10-01), 463-475 |x 1567-567X |q 42:5<463 |1 2015 |2 42 |o 10928 | |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s10928-015-9436-y |q text/html |z Onlinezugriff via DOI |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 900 | 7 | |a Metadata rights reserved |b Springer special CC-BY-NC licence |2 nationallicence | |
| 908 | |D 1 |a research-article |2 jats | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-springer | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1007/s10928-015-9436-y |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Yee |D Sook |u Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Lin |D Lawrence |u Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Merski |D Matthew |u Department of Pharmaceutical Chemistry, University of California San Francisco, 94158-2550, San Francisco, CA, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Keiser |D Michael |u Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Gupta |D Aakash |u Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Zhang |D Youcai |u Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Chien |D Huan-Chieh |u Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Shoichet |D Brian |u Department of Pharmaceutical Chemistry, University of California San Francisco, 94158-2550, San Francisco, CA, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Giacomini |D Kathleen |u Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158-2911, San Francisco, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Journal of Pharmacokinetics and Pharmacodynamics |d Springer US; http://www.springer-ny.com |g 42/5(2015-10-01), 463-475 |x 1567-567X |q 42:5<463 |1 2015 |2 42 |o 10928 | ||