The Orally Active Antihyperglycemic Drug β-Guanidinopropionic Acid Is Transported by the Human Proton-Coupled Amino Acid Transporter hPAT1
| Autor: | Madlen Dorn, Fritz Markwardt, Linda Metzner, Matthias Brandsch |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Amino Acid Transport Systems
Proline Guanidinopropionic acid Glycine Xenopus Pharmaceutical Science Creatine Guanidines chemistry.chemical_compound stomatognathic system Drug Discovery Humans Amino acid transporter Hypolipidemic Agents Molecular Structure Symporters biology Chemistry Glucose transporter Biological Transport Apical membrane biology.organism_classification Electrophysiology Kinetics Biochemistry biology.protein Molecular Medicine Caco-2 Cells GLUT4 |
| Zdroj: | Molecular Pharmaceutics. 6:1006-1011 |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/mp9000684 |
| Popis: | The orally administered creatine analogue beta-guanidinopropionic acid (beta-GPA) decreases plasma glucose levels by increasing the sensitivity to insulin. This effect is based on a beta-GPA induced expression of mRNA and total protein content of the insulin-responsive glucose transporter GLUT4. Although the oral availability of beta-GPA is well established, the underlying uptake mechanism has not yet been studied. We investigated whether the H(+)-coupled amino acid transporter PAT1, which is expressed in the apical membrane of intestinal cells, accepts guanidine derivatives as substrates. Uptake of l-[(3)H]proline into Caco-2 cells expressing hPAT1 constitutively was strongly inhibited by beta-GPA and its derivatives guanidinoacetic acid (GAA) and 4-guanidinobutyric acid (4-GBA). Competition assays revealed apparent affinity constants of about 1.5 mM. Electrophysiological measurements at hPAT1-expressing Xenopus laevis oocytes unequivocally demonstrated that beta-GPA, GAA and 4-GBA are effectively transported by this transport system in an electrogenic manner. We conclude that hPAT1 might be responsible for the intestinal absorption of beta-GPA thereby allowing its oral administration. Moreover, with beta-GPA we identified a new high affinity hPAT1 substrate that might be an interesting starting point for future drug design-drug delivery strategies. |
| Databáze: | OpenAIRE |
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