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

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

Standard

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; Frølund, Sidsel Balsgaard; Ewon, K. B.; Nielsen, A. L.; Brodin, Birger; Jensen, Anne; Kall, M. A.; Nielsen, C U; Christensen, K. V.

In: British Journal of Pharmacology, Vol. 167, No. 3, 2012, p. 654-665.

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

Harvard

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

APA

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

Vancouver

Broberg ML, Holm RK, Tønsberg H, Frølund SB, Ewon KB, Nielsen AL et al. 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. 2012;167(3):654-665. https://doi.org/10.1111/j.1476-5381.2012.02030.x

Author

Broberg, M. L. ; Holm, Rasmus Koldborg ; Tønsberg, H ; Frølund, Sidsel Balsgaard ; Ewon, K. B. ; Nielsen, A. L. ; Brodin, Birger ; Jensen, Anne ; Kall, M. A. ; Nielsen, C U ; Christensen, K. V. / Function and expression of the proton-coupled amino acid transporter Slc36a1 along the rat gastrointestinal tract : Implications for intestinal absorption of gaboxadol. In: British Journal of Pharmacology. 2012 ; Vol. 167, No. 3. pp. 654-665.

Bibtex

@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). The aim is consequently to elucidate the in vivo role of rPAT1 in the absorption of gaboxadol from various intestinal segments. EXPERIMENTAL APPROACH: The absorption of gaboxadol was investigated following administration in four different intestinal segments. The intestinal expression of rSlc36a1 mRNA was measured by quantitative real-time PCR (q-RT-PCR). Furthermore, the hPAT1-/rPAT1-mediated transport of gaboxadol or L-proline was studied in hPAT1-expressing X. 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 administration in the stomach, duodenum and jejunum, but low (4.2%) after administration in the colon. The pharmacokinetics of gaboxadol was modified by the co-administration of L-tryptophan (a hPAT1 inhibitor) and L-proline (a hPAT1 substrate). The in vitro carrier-mediated uptake rate of L-proline in the excised intestinal segments was highest in the mid jejunum and low 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: The results suggest that PAT1 mediates the intestinal absorption of gaboxadol and therefore determines the oral bioavailability. This has implications for the in vivo role of PAT1 and for formulation design of its substrates. {\textcopyright} 2012 The Authors. British Journal of Pharmacology {\textcopyright} 2012 The British Pharmacological Society.",
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",
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",
number = "3",

}

RIS

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.

N1 - © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

PY - 2012

Y1 - 2012

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). The aim is consequently to elucidate the in vivo role of rPAT1 in the absorption of gaboxadol from various intestinal segments. EXPERIMENTAL APPROACH: The absorption of gaboxadol was investigated following administration in four different intestinal segments. The intestinal expression of rSlc36a1 mRNA was measured by quantitative real-time PCR (q-RT-PCR). Furthermore, the hPAT1-/rPAT1-mediated transport of gaboxadol or L-proline was studied in hPAT1-expressing X. 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 administration in the stomach, duodenum and jejunum, but low (4.2%) after administration in the colon. The pharmacokinetics of gaboxadol was modified by the co-administration of L-tryptophan (a hPAT1 inhibitor) and L-proline (a hPAT1 substrate). The in vitro carrier-mediated uptake rate of L-proline in the excised intestinal segments was highest in the mid jejunum and low 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: The results suggest that PAT1 mediates the intestinal absorption of gaboxadol and therefore determines the oral bioavailability. This has implications for the in vivo role of PAT1 and for formulation design of its substrates. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

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). The aim is consequently to elucidate the in vivo role of rPAT1 in the absorption of gaboxadol from various intestinal segments. EXPERIMENTAL APPROACH: The absorption of gaboxadol was investigated following administration in four different intestinal segments. The intestinal expression of rSlc36a1 mRNA was measured by quantitative real-time PCR (q-RT-PCR). Furthermore, the hPAT1-/rPAT1-mediated transport of gaboxadol or L-proline was studied in hPAT1-expressing X. 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 administration in the stomach, duodenum and jejunum, but low (4.2%) after administration in the colon. The pharmacokinetics of gaboxadol was modified by the co-administration of L-tryptophan (a hPAT1 inhibitor) and L-proline (a hPAT1 substrate). The in vitro carrier-mediated uptake rate of L-proline in the excised intestinal segments was highest in the mid jejunum and low 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: The results suggest that PAT1 mediates the intestinal absorption of gaboxadol and therefore determines the oral bioavailability. This has implications for the in vivo role of PAT1 and for formulation design of its substrates. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

U2 - 10.1111/j.1476-5381.2012.02030.x

DO - 10.1111/j.1476-5381.2012.02030.x

M3 - Journal article

C2 - 22577815

VL - 167

SP - 654

EP - 665

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 3

ER -

ID: 38159084