Function and expression of the proton-coupled amino acid transporter Slc36a1 along the rat gastrointestinal tract: Implications for intestinal absorption of gaboxadol

M. L. Broberg; Rasmus Koldborg Holm; H Tønsberg; Sidsel Balsgaard Frølund; K. B. Ewon; A. L. Nielsen; Birger Brodin; Anne Jensen; M. A. Kall; C U Nielsen; K. V. Christensen

doi:10.1111/j.1476-5381.2012.02030.x

Function and expression of the proton-coupled amino acid transporter Slc36a1 along the rat gastrointestinal tract: Implications for intestinal absorption of gaboxadol

M. L. Broberg, Rasmus Koldborg Holm, H Tønsberg, Sidsel Balsgaard Frølund, K. B. Ewon, A. L. Nielsen, Birger Brodin, Anne Jensen, M. A. Kall, C U Nielsen, K. V. Christensen

24 Citations (Scopus)

Abstract

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.

Original language	English
Journal	British Journal of Pharmacology
Volume	167
Issue number	3
Pages (from-to)	654-665
ISSN	0007-1188
DOIs	https://doi.org/10.1111/j.1476-5381.2012.02030.x
Publication status	Published - Oct 2012

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10.1111/j.1476-5381.2012.02030.x

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Broberg, M. L., Holm, R. K., Tønsberg, H., Frølund, S. B., Ewon, K. B., Nielsen, A. L., Brodin, B., Jensen, A., Kall, M. A., Nielsen, C. U., & Christensen, K. V. (2012). Function and expression of the proton-coupled amino acid transporter Slc36a1 along the rat gastrointestinal tract: Implications for intestinal absorption of gaboxadol. British Journal of Pharmacology, 167(3), 654-665. https://doi.org/10.1111/j.1476-5381.2012.02030.x

Function and expression of the proton-coupled amino acid transporter Slc36a1 along the rat gastrointestinal tract : Implications for intestinal absorption of gaboxadol. / Broberg, M. L.; Holm, Rasmus Koldborg; Tønsberg, H et al.

In: British Journal of Pharmacology, Vol. 167, No. 3, 10.2012, p. 654-665.

Research output: Contribution to journal › Journal article › Research › peer-review

Broberg, ML, Holm, RK, Tønsberg, H, Frølund, SB, Ewon, KB, Nielsen, AL, Brodin, B, Jensen, A, Kall, MA, Nielsen, CU & Christensen, KV 2012, 'Function and expression of the proton-coupled amino acid transporter Slc36a1 along the rat gastrointestinal tract: Implications for intestinal absorption of gaboxadol', British Journal of Pharmacology, vol. 167, no. 3, pp. 654-665. https://doi.org/10.1111/j.1476-5381.2012.02030.x

@article{5c3dffe8b44f41cb8378e4d7649cc3b5,

title = "Function and expression of the proton-coupled amino acid transporter Slc36a1 along the rat gastrointestinal tract: Implications for intestinal absorption of gaboxadol",

abstract = "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.",

author = "Broberg, {M. L.} and Holm, {Rasmus Koldborg} and H T{\o}nsberg and Fr{\o}lund, {Sidsel Balsgaard} and Ewon, {K. B.} and Nielsen, {A. L.} and Birger Brodin and Anne Jensen and Kall, {M. A.} and Nielsen, {C U} and Christensen, {K. V.}",

note = "{\textcopyright} 2012 The Authors. British Journal of Pharmacology {\textcopyright} 2012 The British Pharmacological Society.",

year = "2012",

month = oct,

doi = "10.1111/j.1476-5381.2012.02030.x",

language = "English",

volume = "167",

pages = "654--665",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "Wiley",

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TY - JOUR

T1 - Function and expression of the proton-coupled amino acid transporter Slc36a1 along the rat gastrointestinal tract

T2 - Implications for intestinal absorption of gaboxadol

AU - Broberg, M. L.

AU - Holm, Rasmus Koldborg

AU - Tønsberg, H

AU - Frølund, Sidsel Balsgaard

AU - Ewon, K. B.

AU - Nielsen, A. L.

AU - Brodin, Birger

AU - Jensen, Anne

AU - Kall, M. A.

AU - Nielsen, C U

AU - Christensen, K. V.

PY - 2012/10

Y1 - 2012/10

N2 - 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.

AB - 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.

U2 - 10.1111/j.1476-5381.2012.02030.x

DO - 10.1111/j.1476-5381.2012.02030.x

M3 - Journal article

C2 - 22577815

SN - 0007-1188

VL - 167

SP - 654

EP - 665

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 3

ER -

Function and expression of the proton-coupled amino acid transporter Slc36a1 along the rat gastrointestinal tract: Implications for intestinal absorption of gaboxadol

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