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In Vivo Effects of Glycyl-Glutamate and Glycyl-Sarcosine on Gabapentin Oral Absorption in Rat

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Abstract

Purpose

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 C max 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 C max and AUC0–6 h reverted back to that of control. In contrast, the t max 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 AUC0–6 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.

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Abbreviations

AUC0–6 h :

area under the blood concentration vs. time curve from 0–6 h

C max :

maximal blood concentration

GB:

gabapentin

GlyGlu:

glycyl-glutamate

GlySar:

glycyl-sarcosine

IV:

intravenous dosing

RIP:

rat intestinal perfusion

SLC:

solute carrier family

T1/2,λz :

terminal half-life of drug

t max :

time of maximal blood concentration

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Acknowledgments

The authors would like to thank Yatsuhiro Tsume for his generous help with the animal studies. This work was supported in part by Grant R01 GM035498 (D.E.S.) from the National Institutes of Health. Theresa V. Nguyen was supported by an American Foundation for Pharmaceutical Education Fellowship, a Pharmacological Sciences Training Program from the National Institutes of Health (Grant T32 GM007767), and by the College

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Correspondence to Theresa V. Nguyen.

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David Fleisher (deceased) was a co-author of this article.

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Nguyen, T.V., Fleisher, D. & Smith, D.E. In Vivo Effects of Glycyl-Glutamate and Glycyl-Sarcosine on Gabapentin Oral Absorption in Rat. Pharm Res 24, 1538–1543 (2007). https://doi.org/10.1007/s11095-007-9272-x

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  • DOI: https://doi.org/10.1007/s11095-007-9272-x

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