Vigabatrin absorption is mediated via the proton-coupled amino acid transporter PAT1 – in vitro and in vivo

Research output: Contribution to conferencePosterResearch

  • Martha Kampp Nøhr
  • Rasmus Vestergaard Juul
  • Steen Honore' Hansen
  • Larsen, Birger Brodin
  • René Holm
  • Mads Kreilgaard
  • Carsten Uhd Nielsen
The anti-epileptic drug substance vigabatrin is used mainly for the treatment of infantile spasms. In spite of its hydrophilic nature (LogD7.0 ; -2.16), vigabatrin is readily absorbed after oral administration to humans. Vigabatrin has been shown in vitro to be a substrate of the intestinal proton coupled amino acid transporter PAT1, however the actual transport mechanisms involved in transepithelial absorption have not been clarified. The aim of the study was to investigate whether the transepithelial absorption of vigabatrin is mediated by PAT1 – in vitro as well as in vivo.

The absorption of vigabatrin was investigated using Caco-2 cell monolayers and Sprague Dawley rats as an in vitro and in vivo model, respectively. LC-MS or LC-MS/MS was applied for the quantification.

The permeability of vigabatrin in Caco-2 cell monolayers was increased at apical pH 6.0 compared to pH 7.4. The transepithelial transport across Caco-2 cell monolayers was polarized in the lumen-to-blood direction in the presence of a proton gradient. The presence of PAT1-ligands significantly decreased the permeability of vigabatrin across Caco-2 cell monolayers. In Sprague Dawley rats the presence of PAT1-ligands altered the pharmacokinetic profile of vigabatrin with an apparent prolonged absorption of vigabatrin.

Transport of vigabatrin across Caco-2 cell monolayers was polarized in the lumen-to-blood directions, dependent on an acidic pH in the lumen compartment and inhibited by PAT1-ligands. This indicated that PAT1 was the apical entry step in the transepithelial transport pathway. This was supported by in vivo findings, showing that inhibition of PAT1 prolonged the absorption phase of vigabatrin. It is, hence, concluded that PAT1 is involved in vigabatrin transport both in vitro and in vivo.
Original languageEnglish
Publication date24 Jun 2013
Publication statusPublished - 24 Jun 2013

ID: 49330471