Gamma‐aminobutyric acid (GABA) transport across human intestinal epithelial (Caco‐2) cell monolayers

Transintestinal absorption of gamma‐aminobutyric acid (GABA) via a pH‐dependent mechanism is demonstrated in the model human intestinal epithelial cell line Caco‐2. Experiments with BCECF [2′,7′,‐bis(2‐carboxyethyl)‐5(6)‐carboxyfluorescein]‐loaded Caco‐2 cells demonstrate that GABA transport across the apical membrane is coupled to proton flow into the cell. Short‐circuit current (I SC ) measurements using Caco‐2 cell monolayers under voltage‐clamped conditions demonstrate that pH‐dependent GABA transport is a rheogenic process even in the absence of extracellular Na + , consistent with H + /GABA symport. A range of GABA analogues were tested for their abilities to: (a) inhibit pH‐dependent [ 3 H]GABA uptake across the apical membrane; (b) stimulate H + flow across the apical surface of BCECF‐loaded Caco‐2 cell monolayers; (c) increase inward I SC across voltage‐clamped Caco‐2 cell monolayers. Nipecotic acid, isonipecotic acid, D , L ‐β‐aminobutyric acid, and 3‐amino‐1‐propanesulphonic acid each caused a marked acidification of intracellular pH and an increase in I SC when superfused at the apical surface of Caco‐2 cell monolayers. In contrast L ‐α‐amino‐n‐butyric acid failed to induce proton flow or I SC . The ability of these compounds to induce proton or current flow across the apical surface of this intestinal epithelium was closely related to the relative inhibitory effects on [ 3 H]GABA uptake. These observations demonstrate H + /GABA symport and suggest that this transport mechanism may be accessible as a route for oral absorption of therapeutically‐useful GABA analogues.British Journal of Pharmacology (2000) 129 , 457–464; doi: 10.1038/sj.bjp.0703069