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PEPT1 Enhances the Uptake of Gabapentin via Trans-Stimulation of b0,+ Exchange

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Abstract

Purpose

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.

Materials and 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 ≤ 0.01). However, coperfusion of glycylsarcosine (i.e., PEPT1 substrate), methionine sulfoximine (i.e., glutamine synthase inhibitor), or lysine and arginine (i.e., b0,+ 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 b0,+.

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Abbreviations

ala:

alanine

arg:

arginine

GABA:

γ-amino butyric acid

gln:

glutamine

glu:

glutamate

GlyGlu:

glycylglutamate

GlyGly:

glycylglycine

GlySar:

glycylsarcosine

GS:

glutamine synthase

leu:

leucine

lys:

lysine

MS:

methionine sulfoximine

P eff :

effective permeability

SLC:

solute carrier family

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Acknowledgments

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 of Pharmacy (Pfizer and Lyons Fellowships).

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Authors and Affiliations

  1. Deparment of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109-1065, USA

    Theresa V. Nguyen, David E. Smith & David Fleisher

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  1. Theresa V. Nguyen
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  2. David E. Smith
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  3. David Fleisher
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Correspondence to Theresa V. Nguyen.

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This article is posthumous for David Fleisher.

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Nguyen, T.V., Smith, D.E. & Fleisher, D. PEPT1 Enhances the Uptake of Gabapentin via Trans-Stimulation of b0,+ Exchange. Pharm Res 24, 353–360 (2007). https://doi.org/10.1007/s11095-006-9155-6

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  • DOI: https://doi.org/10.1007/s11095-006-9155-6

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