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Rectal Absorption of Vigabatrin, a Substrate of the Proton Coupled Amino Acid Transporter (PAT1, Slc36a1), in Rats

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ABSTRACT

Purpose

To investigate the rectal absorption of vigabatrin in rats, based on the hypothesis that PAT1 (Slc36a1) is involved.

Methods

Male Sprague–Dawley rats were dosed rectally with five different gels, varying in buffer capacity, the amount of vigabatrin, and co-administration of proline or tryptophan. Western blotting was used to detect rPAT1 in rat rectal epithelium. X. Laevis oocytes were injected with SLC36A1 cRNA for the expression of hPAT1, prior to two-electrode voltage clamp measurements.

Results

rPAT1 protein was present in rat rectal epithelium. Approximately 7%–9% of a 1 mg/kg vigabatrin dose was absorbed after rectal administration, regardless of the formulation used. Increasing the dose of vigabatrin 10-fold decreased the absolute bioavailability to 4.2%. Co-administration of proline or tryptophan changed the pharmacokinetic profile, indicating a role of PAT1 in the rectal absorption of vigabatrin. Transport of vigabatrin via hPAT1 expressed in X. Laevis oocytes had a Km of 5.2 ± 0.6 mM and was almost completely inhibited by tryptophan.

Conclusions

Although vigabatrin is a PAT1 substrate and the rPAT1 protein is expressed in the rectum epithelium, vigabatrin has low rectal absorption in rats.

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Abbreviations

GABA:

γ-amino butyric acid

hPAT1:

proton-coupled amino acid transporter human isoform

mPAT1:

proton-coupled amino acid transporter murine isoform

Pro:

L-proline

rGAPDH:

rat glyceraldehyde 3-phosphate dehydrogenase

rPAT1:

proton-coupled amino acid transporter rat isoform

rSlc36a1 :

gene encoding rat solute carrier member 36a1

SLC36A1 :

gene encoding human solute carrier member 36A1

TEVC:

two-electrode voltage clamp

Vig:

vigabatrin

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ACKNOWLEDGMENTS & DISCLOSURES

Kasper Gundel Jensen is acknowledged for skilful technical support with the development of the bioanalytical method and the analysis of the plasma samples. Once again, we are grateful to the staff in the animal facilities for their help and support of our research.

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Authors and Affiliations

  1. Preformulation, H.Lundbeck A/S, Ottiliavej 9, DK-2500, Valby, Denmark

    René Holm & Andreas L. Nielsen

  2. Bioanalysis, H.Lundbeck A/S, Ottiliavej 9, DK-2500, Valby, Denmark

    Morten A. Kall

  3. Department of Pharmaceutics and Analytical Chemistry, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark

    Sidsel Frølund, Andreas L. Nielsen, Anne Jensen, Mie Larsen Broberg & Carsten Uhd Nielsen

Authors
  1. René Holm
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  2. Morten A. Kall
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  3. Sidsel Frølund
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  4. Andreas L. Nielsen
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  5. Anne Jensen
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  6. Mie Larsen Broberg
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  7. Carsten Uhd Nielsen
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Correspondence to Carsten Uhd Nielsen.

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Holm, R., Kall, M.A., Frølund, S. et al. Rectal Absorption of Vigabatrin, a Substrate of the Proton Coupled Amino Acid Transporter (PAT1, Slc36a1), in Rats. Pharm Res 29, 1134–1142 (2012). https://doi.org/10.1007/s11095-012-0673-0

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  • DOI: https://doi.org/10.1007/s11095-012-0673-0

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