Transport of pregabalin in rat intestine and Caco-2 monolayers

Purpose. The purpose of this study was to determine if the intestinal trans port of pregabalin (isobutyl gamma-aminobutyric acid, isobutyl GABA), a new anticonvulsant drug, was mediated by amino acid carriers with affinity for large neutral amino acids (LNAA). Methods. Pregabalin transport was studied in mt intestine and Caco-2 monola yers. An in vitro Ussing/diffusion chamber model and an in situ single-pass perfusion model were used to study mt intestinal transport. An in vitro di ffusion chamber model was used to evaluate Caco-2 transport. Results. In rat ileum, pregabalin transport was saturable and inhibited by substrates of intestinal LNAA carriers including neurontin (gabapentin), ph enylalanine, and proline. Weak substrates of intestinal LNAA carriers (beta -alanine, gamma-aminobutyric acid, and methyl aminoisobutyric acid) did not significantly change pregabalin transport. In Caco-2 monolayers that showe d a high capacity for phenylalanine transport, pregabalin transport was con centration- and direction-independent and equivalent in magnitude to the pa racellular marker, mannitol. The in,? vitro and in situ rat ileal permeabil ities of the LNAA carrier-mediated compounds neurontin, pregabalin, and phe nylalanine correlated well with the corresponding in vivo human oral absorp tion. Conclusions. The transport of pregabalin was mediated by LNAA carriers in r at ileum but not in Caco-2 monolayers. Caco-2 was not an appropriate model for evaluating the in vivo human oral absorption of pregabalin and neuronti n.