title: Function and expression of the proton-coupled amino acid transporter PAT1 along the rat gastrointestinal tract: implications for intestinal absorption of gaboxadol.
abstract: OBJECTIVE
  Intestinal absorption via membrane transporters may determine the pharmacokinetics of drug compounds. The hypothesis is that oral absorption of gaboxadol (4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol) in rats occurs via the proton-coupled amino acid transporter, rPAT1 (encoded by the gene rSlc36a1). Consequently, we aimed to elucidate the in vivo role of rPAT1 in the absorption of gaboxadol from various intestinal segments obtained from Sprague-Dawley rats.
  
  
  METHODS
  The absorption of gaboxadol was investigated following its administration into four different intestinal segments. The intestinal expression of rSlc36a1 mRNA was measured by quantitative real-time PCR. Furthermore, the hPAT1-/rPAT1-mediated transport of gaboxadol or L-proline was studied in hPAT1-expressing Xenopus laevis oocytes, Caco-2 cell monolayers and excised segments of the rat intestine.
  
  
  RESULTS
  The absorption fraction of gaboxadol was high (81.3-91.3%) following its administration into the stomach, duodenum and jejunum, but low (4.2%) after administration into the colon. The pharmacokinetics of gaboxadol were modified by the co-administration of L-tryptophan (an hPAT1 inhibitor) and L-proline (an hPAT1 substrate). The in vitro carrier-mediated uptake rate of L-proline in the excised intestinal segments was highest in the mid jejunum and lowest in the colon. The in vitro uptake and the in vivo absorption correlated with the expression of rSlc36a1 mRNA along the rat intestine.
  
  
  CONCLUSIONS
  These results suggest that PAT1 mediates the intestinal absorption of gaboxadol and therefore determines its oral bioavailability. This has implications for the in vivo role of PAT1 and may have an influence on the design of pharmaceutical formulations of PAT1 substrates.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: M l
authors.initials: Ml
authors.lastname: Broberg
authors.forename: R
authors.initials: R
authors.lastname: Holm
authors.forename: H
authors.initials: H
authors.lastname: Tønsberg
authors.forename: S
authors.initials: S
authors.lastname: Frølund
authors.forename: K B
authors.initials: KB
authors.lastname: Ewon
authors.forename: A l
authors.initials: Al
authors.lastname: Nielsen
authors.forename: B
authors.initials: B
authors.lastname: Brodin
authors.forename: A
authors.initials: A
authors.lastname: Jensen
authors.forename: M A
authors.initials: MA
authors.lastname: Kall
authors.forename: K V
authors.initials: KV
authors.lastname: Christensen
authors.forename: C U
authors.initials: CU
authors.lastname: Nielsen
mesh_terms: D000284:Administration, Oral; D026905:Amino Acid Transport Systems / Q000235:genetics / Q000378:metabolism*; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D018938:Caco-2 Cells; D041981:Gastrointestinal Tract / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption; D007555:Isoxazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D011392:Proline / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014364:Tryptophan / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D026905:Amino Acid Transport Systems; D026921:Amino Acid Transport Systems, Neutral; D007555:Isoxazoles; D012333:RNA, Messenger; C475905:SLC36A1 protein, human; C493537:Slc36a1 protein, rat; D027981:Symporters; D014364:Tryptophan; D011392:Proline; C015542:gaboxadol