Acamprosate has no impact on the permeability of paracellular markers across Caco-2 cells

Backgrounds: The oral bioavailability of poorly permeable and non-metabolised acamprosate (BCS III) is 11%. It is controversial whether the intestinal effective permeability of the fully an-ionized acamprosate (pKa 1.83; MW 181.2 g/mol) is predominantly paracellular (Ppara) or transcellular. An initial physiologically-based pharmacokinetic model indicates that Ppara can’t account for acamprosate absorption and suggests involvement of carrier-mediated transport. However, an alternative explanation could be that acamprosate enhances its own Ppara. Aims: The effect of acamprosate on Ppara of the paracellular markers, mannitol and Lucifer Yellow (LY), was investigated.
Methods: Ppara of LY and [14C]-mannitol was investigated across filter grown human epithelial colorectal adenocarcinoma (Caco-2) cell monolayers. Changes in the transepithelial electrical resistance (TEER) across the monolayers were evaluated. Results: LY and [14C]-mannitol Ppara values were not significantly different in presence 0.43±0.06x10-6 and 0.47±0.24x10-6 cm/s or absence 0.30±0.08x10-6 and 0.43±0.20x10-6 cm/s (Mean±SD, n=3) of acamprosate, respectively. Pre-treated cells with acamprosate for 24 or 4 hours before applying the [14C]-mannitol, Papp values of 0.71±0.2x10-6 and 0.51±0.17x10-6 cm/s were obtained. TEER values at the end of all experiments were in the range of 426-444 ohm*cm2. Summary/Conclusion: Acamprosate has no impact on the paracellular pathway across Caco-2 cell monolayers of LY and mannitol, or on the TEER values. This consolidates the hypothesis that intestinal transporters might play a role in the absorption of acamprosate.