Introduction: Many drug substances are substrates for membrane transporters, which influence their intestinal absorption. Vigabatrin is a drug substance used in the treatment of epilepsy, mainly for treatment of infantile spasms. Vigabatrin is a substrate for the human proton-coupled amino acid transporter hPAT1. The aim of the project was to identify if transporters are involved in cellular uptake of vigabatrin in Caco-2 cells.

Methods: The uptake rate of vigabatrin was measured in Caco-2 cells at pH 6.0 or 7.4 for 15 min after application of 0.1 – 25.0 mM vigabatrin. The inhibitory effect of selected amino acids and -derivatives on the apical vigabatrin uptake in Caco-2 cells was investigated. Vigabatrin samples were analyzed using liquid chromatography (LC) coupled to a mass selective detector (MSD).

Results: The uptake rate of vigabatrin in Caco-2 cells was pH-dependent. The uptake of vigabatrin was saturable at pH 6.0 with a Michaelis constant, Km of 12.7 ± 3.7 mM and a maximal flux, Jmax of 3.7 ± 0.5 nmol•min-1•cm-2. The presences of hPAT1 ligands significantly inhibited the uptake of vigabatrin in Caco-2 cells at pH 6.0, whereas hPAT1 non-ligands did not.

Discussion: The saturability of the uptake at pH 6.0 indicates involvement of a carrier-mediated process in vigabatrin absorption. The pH-dependency of the vigabatrin uptake suggests that the uptake may be driven by a proton-coupled transporter. The Km-value is comparable to Km- values for other hPAT1 substrates (1-20 mM). The interaction of hPAT1 ligands with the uptake is a further indication of hPAT1 involvement in vigabatrin absorption. It is concluded that the proton-coupled amino acid transporter hPAT1 is the main transporter responsible for absorption of vigabatrin in Caco-2 cells.