In-vitro investigation regarding the effects of Gelucire® 44/14 and Labrasol® ALF on the secretory intestinal transport of P-gp substrates

In this present study, the secretory transport of P-gp substrates, rhodamine 123 and digoxin, was evaluated using a Caco-2/HT29-MTX co-culture characterized by an efflux mechanism and a paracellular permeability closer to the human intestinal barrier compared to the Caco-2 monolayer gold standard. The influence of simulated intestinal fluids termed FeSSIF and FaSSIF on the intestinal absorption was also assessed in comparison with a conventional saline buffer. Labrasol (R) ALF and Gelucire (R) 44/14 in saline buffer significantly decreased to 83% and 62%, the P-gp-mediated transport of rhodamine 123 across the co-culture, respectively. The effects of Gelucire (R) 44/14 were much more exacerbated with the Caco-2 monolayer model with a reduced permeability to 34% but they were partially reversed in the co-culture with FeSSIF. The modulation by the lipid excipients of digoxin secretory transport across the Caco-2 monolayer and the co-culture was reduced compared with the rhodamine 123. This work also emphasizes the numerous parameters that have to be considered for predicting accurately the effects of potential P-gp inhibitors including the in-vitro model, the incubation media and the intrinsic properties of P-gp substrates. (C) 2016 Elsevier B.V. All rights reserved.