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

British Journal of Pharmacology
Mie Larsen BrobergCarsten Uhd Nielsen

Abstract

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. 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. 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 ...Continue Reading

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Citations

Oct 23, 2014·Therapeutic Delivery·Martha Kampp NøhrCarsten Uhd Nielsen
Dec 22, 2015·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Martin KuentzDavid P Elder
Dec 4, 2015·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Rune Nørgaard RasmussenCarsten Uhd Nielsen
Aug 22, 2013·British Journal of Pharmacology·C U NielsenR Holm
Jan 7, 2015·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·M K NøhrC U Nielsen
Nov 14, 2013·American Journal of Physiology. Endocrinology and Metabolism·Anne JensenCarsten Uhd Nielsen
Mar 16, 2013·The Journal of Pharmacy and Pharmacology·Valerie VoigtMatthias Brandsch
Nov 26, 2019·American Journal of Physiology. Gastrointestinal and Liver Physiology·Yuxin ChenChristian Lytle
Jun 3, 2020·Nature Nanotechnology·Xiangfei HanZhiqiang Cao
Dec 19, 2020·The Journal of Biological Chemistry·Yoshiko MurataKosuke Namba

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