Intestinal drug transport via the proton-coupled amino acid transporter PAT1 (SLC36A1) is inhibited by Gly-X(aa) dipeptides.

The oral absorption of some drug substances is mediated by nutrient transporters. As a consequence, nutrients and drugs may compete for available transporters, and interactions at the level of intestinal absorption are possible. Recently, we have identified δ-aminolevulinic acid, Gly-Gly, and Gly-Sar as substrates of the amino acid transporter PAT1. The aim of the present study is to investigate if other Gly-containing dipeptides interact with PAT1, and whether they can inhibit PAT1 mediated drug absorption, in vitro and in vivo. The in vitro methods included two-electrode voltage clamp measurements on hPAT1 expressing Xenopus laevis oocytes, which were used to investigate the PAT1-mediated transport of 17 different Gly-containing dipeptides (Gly-X(aa) or X(aa)-Gly). Also, the transepithelial transport of the PAT1 substrate gaboxadol was investigated across Caco-2 cell monolayers in the presence of different dipeptides. The in vivo part consisted of a pharmacokinetic study in rats following oral administration of gaboxadol and preadministration of 200 mg/kg dipeptide. The results showed that in hPAT1 expressing oocytes Gly-Tyr, Gly-Pro, and Gly-Phe inhibited currents induced by drug substances. In Caco-2 cell monolayers, Gly-Gly, Gly-Sar, and Gly-Pro significantly inhibited the PAT1 mediated absorptive transepithelial transport of gaboxadol; however, when orally administered to rats, Gly-Gly, Gly-Sar, Gly-Pro, or Gly-Tyr did not alter the pharmacokinetic profile of gaboxadol. In conclusion, the present study identifies selected dipeptides as inhibitors of PAT1 mediated drug absorption in various in vitro models.