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