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In vivo and In vitro Evaluations of Intestinal Gabapentin Absorption: Effect of Dose and Inhibitors on Carrier-Mediated Transport

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Abstract

Purpose

Gabapentin exhibits saturable absorption kinetics, however, it remains unclear which transporters that are involved in the intestinal transport of gabapentin. Thus, the aim of the current study was to explore the mechanistic influence of transporters on the intestinal absorption of gabapentin by both in vivo and in vitro investigations

Methods

Pharmacokinetic parameters were determined following a range of intravenous (5–100 mg/kg) and oral doses (10–200 mg/kg) in rats. Transepithelial transport (50 μM–50 mM) and apical uptake of gabapentin (0.01–50 mM) were investigated in Caco-2 cells. The effect of co-application of the LAT-inhibitor, BCH, and the b0,+-substrate, L-lysine, on intestinal transport of gabapentin was evaluated in vivo and in vitro.

Results

Gabapentin showed dose-dependent oral absorption kinetics and dose-independent disposition kinetics. Co-application of BCH inhibited intestinal absorption in vivo and apical uptake in vitro, whereas no effect was observed following co-application of L-lysine.

Conclusions

The present study shows for the first time that BCH was capable of inhibiting intestinal absorption of gabapentin in vivo. Furthermore, in Caco-2 cell experiments BCH inhibited apical uptake of gabapentin. These findings may imply that a BCH-sensitive transport-system was involved in the apical and possibly the basolateral transport of gabapentin across the intestinal wall.

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Abbreviations

GBP:

Gabapentin

BBB:

Blood–brain barrier

Leu:

L-Leucine

Phe:

L-Phenylalanine

Lys:

L-Lysine

Arg:

L-Arginine

CssC:

L-Cystine

BCH:

2-amino-2-norbornanecarboxylic acid

(A-B):

Apical to basolateral

(B-A):

Basolateral to apical

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ACKNOWLEDGMENTS AND DISCLOSURES

The personnel at the animal facilities at H. Lundbeck A/S are acknowledged and appreciated for their skillful and flexible handling of the animal study. The cell culture facility at Department of Pharmacy is acknowledged for culturing cells.

Author information

Authors and Affiliations

  1. Biologics and Pharmaceutical Science, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark

    Malte Selch Larsen & René Holm

  2. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark

    Malte Selch Larsen & Mads Kreilgaard

  3. Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark

    Sidsel Frølund, Martha Kampp Nøhr, Carsten Uhd Nielsen & René Holm

  4. Discovery DMPK, H. Lundbeck A/S, Ottiliavej 9, DK-2500, Valby, Denmark

    Mats Garmer

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  1. Malte Selch Larsen
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Correspondence to René Holm.

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Larsen, M.S., Frølund, S., Nøhr, M.K. et al. In vivo and In vitro Evaluations of Intestinal Gabapentin Absorption: Effect of Dose and Inhibitors on Carrier-Mediated Transport. Pharm Res 32, 898–909 (2015). https://doi.org/10.1007/s11095-014-1505-1

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  • DOI: https://doi.org/10.1007/s11095-014-1505-1

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