PEPT1 enhances the uptake of gabapentin via trans-stimulation of b0,+ exchange.
OBJECTIVE
The aims of this study were (1) to determine whether amino acid and dipeptide loading can improve the effective permeability of gabapentin and (2) to characterize the underlying mechanism that is responsible for this interaction.


METHODS
An in situ single-pass rat intestinal perfusion model was used to assess the effective permeability of gabapentin in rat, in the absence and presence of cellular loading by amino acid and dipeptide mixtures.


RESULTS
Compared to gabapentin alone, cellular loading with amino acid and dipeptide mixtures significantly improved the effective permeability of gabapentin by 46-79% in jejunum and by 67-72% in ileum (p < or = 0.01). However, coperfusion of glycylsarcosine (i.e., PEPT1 substrate), methionine sulfoximine (i.e., glutamine synthase inhibitor), or lysine and arginine (i.e., b(0,+) substrates) with the amino acid and dipeptide mixtures compromised the intestinal uptake of gabapentin.


CONCLUSIONS
These findings demonstrate, for the first time, a direct relationship between the PEPT1-mediated uptake of a dipeptide and the trans-stimulated uptake of gabapentin (an amino acid-like drug) through the transport system b(0,+).
Nguyen
Theresa V
TV
Deparment of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109-1065, USA. tvnguyen@umich.edu
Smith
David E
DE
Fleisher
David
D
D000588:Amines / Q000378:metabolism*; D026905:Amino Acid Transport Systems / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001693:Biological Transport, Active; D003509:Cyclohexanecarboxylic Acids / Q000378:metabolism*; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology; D000077206:Gabapentin; D005947:Glucose / Q000494:pharmacology; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008239:Lysine / Q000494:pharmacology; D008297:Male; D000074011:Peptide Transporter 1; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D027981:Symporters / Q000494:pharmacology*; D014867:Water / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000588:Amines; D026905:Amino Acid Transport Systems; D000596:Amino Acids; D003509:Cyclohexanecarboxylic Acids; D004151:Dipeptides; D000074011:Peptide Transporter 1; D027981:Symporters; D014867:Water; C004194:glycylsarcosine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D001120:Arginine; D012964:Sodium; D005974:Glutamate-Ammonia Ligase; D005947:Glucose; D008239:Lysine