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

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Abbot EL, Grenade DS, Kennedy DJ, Gatfield KM, Thwaites DT

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

Br J Pharmacol. 2006 Feb;147(3):298-306.

PubMed ID

16331283 [ View in PubMed

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Abstract

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). The Caco-2 cell line was used as a model of the human small intestinal epithelium. Competition experiments demonstrate that [3H]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. Experiments with 2',7'-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. In hPAT1 and mPAT1-expressing Xenopus laevis oocytes [3H]GABA uptake was inhibited by vigabatrin, TACA and guvacine, whereas gabapentin failed to inhibit [3H]GABA uptake. 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 [3H]GABA uptake. 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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Vigabatrin	Proton-coupled amino acid transporter 1	Protein	Humans	Unknown	Substrate	Details