BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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 AND IMPLICATIONS 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.

Addition of PS80 to the formulation increased the bioavailability of halofantrine and the more compound, the more PS80 was needed to prevent precipitation.

The single bile duct cannulated rat model was used for short-term intestinal absorption studies. Rats were randomly assigned to three groups: (A) bile duct cannulated, (B) control laparotomy and (C) no treatment. The body weight and health of the rats were monitored before and until day 5 after surgery, while bile flow was measured in group A on day 2. On the fifth day, tail vein blood was harvested, and alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin were quantified. Analysis of variance showed no significant difference between the groups for these parameters. This study demonstrated the suitability of a surgical rat model feasible for evaluation of the impact of bile in pharmacokinetic studies.