Function and expression of the proton‐coupled amino acid transporter PAT1 along the rat gastrointestinal tract: implications for intestinal absorption of gaboxadol

<jats:p><jats:bold>BACKGROUND AND PURPOSE</jats:bold> 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 <jats:italic>rSlc36a1</jats:italic>). Consequently, we aimed to elucidate the <jats:italic>in vivo</jats:italic> role of rPAT1 in the absorption of gaboxadol from various intestinal segments obtained from Sprague‐Dawley rats.</jats:p><jats:p><jats:bold>EXPERIMENTAL APPROACH</jats:bold> The absorption of gaboxadol was investigated following its administration into four different intestinal segments. The intestinal expression of <jats:italic>rSlc36a1</jats:italic> mRNA was measured by quantitative real‐time PCR. Furthermore, the hPAT1‐/rPAT1‐mediated transport of gaboxadol or L‐proline was studied in hPAT1‐expressing <jats:italic>Xenopus laevis</jats:italic> oocytes, Caco‐2 cell monolayers and excised segments of the rat intestine.</jats:p><jats:p><jats:bold>KEY RESULTS</jats:bold> 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 <jats:italic>in vitro</jats:italic> carrier‐mediated uptake rate of L‐proline in the excised intestinal segments was highest in the mid jejunum and lowest in the colon. The <jats:italic>in vitro</jats:italic> uptake and the <jats:italic>in vivo</jats:italic> absorption correlated with the expression of <jats:italic>rSlc36a1</jats:italic> mRNA along the rat intestine.</jats:p><jats:p><jats:bold>CONCLUSIONS AND IMPLICATIONS</jats:bold> These results suggest that PAT1 mediates the intestinal absorption of gaboxadol and therefore determines its oral bioavailability. This has implications for the <jats:italic>in vivo</jats:italic> role of PAT1 and may have an influence on the design of pharmaceutical formulations of PAT1 substrates.</jats:p>