| Title |
Prediction and validation of enzyme and transporter off-targets for metformin
|
|---|---|
| Published in |
Journal of Pharmacokinetics and Pharmacodynamics, September 2015
|
| DOI | 10.1007/s10928-015-9436-y |
| Pubmed ID | |
| Authors |
Sook Wah Yee, Lawrence Lin, Matthew Merski, Michael J. Keiser, Aakash Gupta, Youcai Zhang, Huan-Chieh Chien, Brian K. Shoichet, Kathleen M. Giacomini |
| 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. |
X Demographics
The data shown below were collected from the profile of 1 X user who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 60 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 60 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 8 | 13% |
| Researcher | 7 | 12% |
| Student > Master | 6 | 10% |
| Student > Bachelor | 5 | 8% |
| Other | 5 | 8% |
| Other | 9 | 15% |
| Unknown | 20 | 33% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 12 | 20% |
| Pharmacology, Toxicology and Pharmaceutical Science | 6 | 10% |
| Biochemistry, Genetics and Molecular Biology | 6 | 10% |
| Agricultural and Biological Sciences | 5 | 8% |
| Unspecified | 1 | 2% |
| Other | 7 | 12% |
| Unknown | 23 | 38% |
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 17 March 2024.
All research outputs
#16,812,059
of 25,503,365 outputs
Outputs from Journal of Pharmacokinetics and Pharmacodynamics
#328
of 481 outputs
Outputs of similar age
#157,209
of 277,217 outputs
Outputs of similar age from Journal of Pharmacokinetics and Pharmacodynamics
#6
of 10 outputs
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