title: In-vitro investigation regarding the effects of Gelucire®44/14 and Labrasol® ALF on the secretory intestinal transport of P-gp substrates.
abstract: 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®ALF and Gelucire®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®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.
authors.affiliation: FDE EA4267, Univ. Bourgogne Franche-Comté, F-25000, Besançon, France.
authors.forename: Océane
authors.initials: O
authors.lastname: Dubray
authors.affiliation: Gattefossé SAS, 36 chemin de Genas, 69804, Saint-Priest cedex, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jannin
authors.affiliation: Gattefossé SAS, 36 chemin de Genas, 69804, Saint-Priest cedex, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Demarne
authors.affiliation: FDE EA4267, Univ. Bourgogne Franche-Comté, F-25000, Besançon, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Pellequer
authors.affiliation: FDE EA4267, Univ. Bourgogne Franche-Comté, F-25000, Besançon, France; Department of Pharmaceutics, Institute of Pharmacy, University of Bonn, Germany.
authors.forename: Alf
authors.initials: A
authors.lastname: Lamprecht
authors.affiliation: FDE EA4267, Univ. Bourgogne Franche-Comté, F-25000, Besançon, France. Electronic address: arnaud.beduneau@univ-fcomte.fr.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Béduneau
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D018920:Coculture Techniques / Q000379:methods; D004077:Digoxin / Q000378:metabolism; D005079:Excipients / Q000737:chemistry; D005989:Glycerides / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D010539:Permeability / Q000187:drug effects; D011092:Polyethylene Glycols / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005079:Excipients; D005989:Glycerides; D008055:Lipids; C440220:Labrasol; C104509:gelucire 44-14; D020112:Rhodamine 123; D011092:Polyethylene Glycols; D004077:Digoxin
keywords: Caco-2/HT29-MTX co-culture; Digoxin; Gelucire(®); Intestinal barrier; Labrasol(®); P-glycoprotein; Permeability