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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

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

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 [(3)H]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 [(3)H]GABA uptake was inhibited by vigabatrin, TACA and guvacine, whereas gabapentin failed to inhibit [(3)H]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 [(3)H]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.British Journal of Pharmacology (2006) 147, 298-306. doi:10.1038/sj.bjp.0706557; published online 5 December 2005.[1]

References

  1. Vigabatrin transport across the human intestinal epithelial (Caco-2) brush-border membrane is via the H(+)-coupled amino-acid transporter hPAT1. Abbot, E.L., Grenade, D.S., Kennedy, D.J., Gatfield, K.M., Thwaites, D.T. Br. J. Pharmacol. (2006) [Pubmed]
 
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