In vivo effects of glycyl-glutamate and glycyl-sarcosine on gabapentin oral absorption in rat.
OBJECTIVE
The objective of this study was to evaluate the in vivo consequences of glycyl-glutamate coadministration on gabapentin oral absorption.


METHODS
Rats were administered gabapentin (10 mg/kg plus radiotracer) by gastric gavage, in the absence and presence of dipeptides, and by intravenous administration. Serial blood samples were obtained over 6 h and the pharmacokinetics of gabapentin were determined by noncompartmental analysis.


RESULTS
Glycyl-glutamate coadministration increased the Cmax of gabapentin by 86% as compared to gabapentin alone. In agreement, the oral absorption of gabapentin, relative to the intravenous dose, was 79% after glycyl-glutamate loading but only 47% when drug was administered alone. However, when glycyl-sarcosine was added to the orally administered admixture of gabapentin plus glycyl-glutamate, values for Cmax and AUC(0-6 h) reverted back to that of control. In contrast, the tmax and terminal half-life of gabapentin did not change after oral dosing for all treatments.


CONCLUSIONS
These findings are unique in demonstrating that under physiologic, in vivo conditions, the luminal presence of glycyl-glutamate could dramatically enhance the Cmax and AUC(0-6 h) of gabapentin. The results are consistent with previous in situ intestinal perfusion studies in rat, and establish a functional interaction between the activities of PEPT1 and amino acid exchangers.
Nguyen
Theresa V
TV
Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, Michigan 48109-1065, USA. tvnguyen@umich.edu
Fleisher
David
D
Smith
David E
DE
D000284:Administration, Oral; D000588:Amines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D026905:Amino Acid Transport Systems / Q000378:metabolism; D000700:Analgesics / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology*; D000077206:Gabapentin; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000588:Amines; D026905:Amino Acid Transport Systems; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D004151:Dipeptides; C004194:glycylsarcosine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; C046223:N-glycylglutamic acid