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Vigabatrin transport across the human intestinal epithelial (Caco-2) brush-border membrane is via the H+-coupled amino-acid transporter hPAT1

Lookup NU author(s): Dr Emily Abbot, Danielle Grenade, Professor David Kennedy, Kelly Gatfield, Professor David Thwaites


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1 The aim of this investigation was to determine if the human proton-coupled amino-acid transporter 1 (hPAT1 or SLC36A1) is responsible for the intestinal uptake of the orally-administered antiepileptic agent 4-amino-5-hexanoic acid (vigabatrin). 2 The Caco-2 cell line was used as a model of the human small intestinal epithelium. Competition experiments demonstrate that [H-3] GABA uptake across the apical membrane was inhibited by vigabatrin and the GABA analogues trans-4-aminocrotonic acid ( TACA) and guvacine, whereas 1-(aminomethyl) cyclohexaneacetic acid ( gabapentin) had no affect. 3 Experiments with 20,70-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)-loaded Caco-2 cells demonstrate that apical exposure to vigabatrin and TACA induce comparable levels of intracellular acidification (due to H+/amino-acid symport) to that generated by GABA, suggesting that they are substrates for a H+-coupled absorptive transporter such as hPAT1. 4 In hPAT1 and mPAT1-expressing Xenopus laevis oocytes [H-3] GABA uptake was inhibited by vigabatrin, TACA and guvacine, whereas gabapentin failed to inhibit [H-3] GABA uptake. 5 In Na+-free conditions, vigabatrin and TACA evoked similar current responses (due to H+/amino-acid symport) in hPAT1-expressing oocytes under voltage-clamp conditions to that induced by GABA ( whereas no current was observed in water-injected oocytes) consistent with the ability of these GABA analogues to inhibit [H-3] GABA uptake. 6 This study demonstrates that hPAT1 is the carrier responsible for the uptake of vigabatrin across the brush-border membrane of the small intestine and emphasises the therapeutic potential of hPAT1 as a delivery route for orally administered, clinically significant GABA-related compounds.

Publication metadata

Author(s): Abbot EL, Grenade DS, Kennedy DJ, Gatfield KM, Thwaites DT

Publication type: Article

Publication status: Published

Journal: British Journal of Pharmacology

Year: 2006

Volume: 147

Issue: 3

Pages: 298-306

ISSN (print): 0007-1188

ISSN (electronic): 1476-5381

Publisher: John Wiley & Sons Ltd.


DOI: 10.1038/sj.bjp.0706557


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