The Orally Active Antihyperglycemic Drug β-Guanidinopropionic Acid Is Transported by the Human Proton-Coupled Amino Acid Transporter hPAT1

The orally administered creatine analogue β-guanidinopropionic acid (β-GPA) decreases plasma glucose levels by increasing the sensitivity to insulin. This effect is based on a β-GPA induced expression of mRNA and total protein content of the insulin-responsive glucose transporter GLUT4. Although the oral availability of β-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-[3H]proline into Caco-2 cells expressing hPAT1 constitutively was strongly inhibited by β-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 β-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 β-GPA thereby allowing its oral administration. Moreover, with β-GPA we identified a new high affinity hPAT1 substrate that might be an interesting starting point for future drug design-drug delivery strategies.