Transport of pregabalin in rat intestine and Caco-2 monolayers.
OBJECTIVE
The purpose of this study was to determine if the intestinal transport 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 rat intestine and Caco-2 monolayers. An in vitro Ussing/diffusion chamber model and an in situ single-pass perfusion model were used to study rat intestinal transport. An in vitro diffusion 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), phenylalanine, 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 showed a high capacity for phenylalanine transport, pregabalin transport was concentration- and direction-independent and equivalent in magnitude to the paracellular marker, mannitol. The in vitro and in situ rat ileal permeabilities of the LNAA carrier-mediated compounds neurontin, pregabalin, and phenylalanine correlated well with the corresponding in vivo human oral absorption.


CONCLUSIONS
The transport of pregabalin was mediated by LNAA carriers in rat 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 neurontin.
Jezyk
N
N
College of Pharmacy, The University of Michigan, Ann Arbor 48109-1065, USA.
Li
C
C
Stewart
B H
BH
Wu
X
X
Bockbrader
H N
HN
Fleisher
D
D
D000085:Acetates / Q000493:pharmacokinetics; D000588:Amines; D000596:Amino Acids / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D003106:Colon / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids; D000077206:Gabapentin; D006801:Humans; D007082:Ileum / Q000378:metabolism; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008353:Mannitol / Q000493:pharmacokinetics; D010649:Phenylalanine / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000069583:Pregabalin; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D000085:Acetates; D000588:Amines; D000596:Amino Acids; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D008353:Mannitol; D010649:Phenylalanine; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin