title: Intestinal drug transport via the proton-coupled amino acid transporter PAT1 (SLC36A1) is inhibited by Gly-X(aa) dipeptides.
abstract: 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.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Sidsel
authors.initials: S
authors.lastname: Frølund
authors.forename: Louise
authors.initials: L
authors.lastname: Langthaler
authors.forename: Morten A
authors.initials: MA
authors.lastname: Kall
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.forename: Carsten Uhd
authors.initials: CU
authors.lastname: Nielsen
mesh_terms: D000284:Administration, Oral; D026905:Amino Acid Transport Systems / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D005998:Glycine / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000378:metabolism*; D014982:Xenopus laevis / Q000378:metabolism
chemical_list: D026905:Amino Acid Transport Systems; D004151:Dipeptides; D007555:Isoxazoles; D011522:Protons; C475905:SLC36A1 protein, human; D027981:Symporters; C004194:glycylsarcosine; C015248:glycylproline; C029660:glycylphenylalanine; C022013:glycyltyrosine; C015542:gaboxadol; D005998:Glycine