Sodium glycodeoxycholate and sodium deoxycholate as epithelial permeation enhancers: in vitro and ex vivo intestinal and buccal bioassays.

Bile salts were first tested as epithelial permeation enhancers (PEs) for the intestine and buccal routes over 20 years ago. They are not as popular as other PEs due to their non-specific mechanism of action and perceived toxicity potential. We revisited two of them by comparing efficacy and toxicity of sodium glycodeoxycholate (SGC) and sodium deoxycholate (DC) for both routes using in vitro and ex vivo methods. Cytotoxicity assays in Caco-2 cells revealed that both agents altered cellular parameters at concentrations >2 mM over 60 min. Both agents reduced the transepithelial resistance (TEER) and doubled the Papp of [3H]-octreotide across isolated rat colonic mucosae mounted in Ussing chambers at 10 mM concentrations. In some studies, 10 mM GDC also increased the Papp of the paracellular marker, FITC-dextran 4000 (FD4) and the fluorescent peptide, FITC-LKP, across colonic mucosae. Tissue histology was intact despite some mild perturbation at 10 mM. In the buccal epithelial cell line, TR146, changes in cell parameters were also seen at 1.5 mM over 60 min for both agents, with slightly more sensitivity seen for DC. In isolated porcine buccal epithelial mucosae, GDC was slightly more potent and efficacious than DC at increasing the Papp of [14C]-mannitol. It also increased the Papp of [3H]-octreotide and FITC-LKP by ∼3-fold across porcine buccal tissue without causing damage. Overall, GDC and DC were efficacious in intestinal and buccal models. Both cause mild perturbation leading to an increase in paracellular fluxes for hydrophilic molecules including peptides. Their moderate efficacy, low potency, and low toxicity in these models are similar to that of more established PEs in clinical trials.