title: Modulation of intestinal barrier properties by miltefosine.
abstract: Miltefosine (hexadecylphosphocholine, HePC) is the first effective oral agent for the treatment of visceral leishmaniasis. This study aimed to determine whether this oral administration alters the integrity and transport capacities of the intestinal barrier. The objectives of this study were: (i) to evaluate the cytotoxicity of HePC, (ii) to investigate the effects of HePC on paracellular and transcellular transport and (iii) to investigate the influence of HePC on three major transporters of the intestinal barrier, namely, P-glycoprotein, the human intestinal peptide transporter (PepT-1) and the monocarboxylic acid transporter (MCT-1) in Caco-2 cell monolayers, used as an in vitro model of the human intestinal barrier. We show that HePC reduced the transepithelial electrical resistance and increased D-[14C]mannitol permeability in a dose-dependent manner but had no effect on [3H]testosterone permeability, demonstrating that HePC treatment enhances paracellular permeability via an opening of the tight junction complex without affecting the transcellular route. Morphological studies using confocal fluorescence microscopy showed no perturbation of the normal distribution of ZO-1, occludin or E-cadherin but revealed a redistribution of the tight junction-associated protein claudin-1 and the perijunctional actin after incubation with HePC. Finally, HePC was found to inhibit the intestinal P-glycoprotein in the Caco-2 cell model after a single short exposure. These results suggest that HePC could modify the oral bioavailability of other therapeutic compounds absorbed via the paracellular route or which are substrates of the intestinal P-glycoprotein.
authors.affiliation: Laboratoire de Physico-chimie, Pharmacotechnie et Biopharmacie, UMR CNRS 8612, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France. cecile.menez@cep.u-psud.fr
authors.forename: Cécile
authors.initials: C
authors.lastname: Menez
authors.forename: Marion
authors.initials: M
authors.lastname: Buyse
authors.forename: Hélène
authors.initials: H
authors.lastname: Chacun
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.forename: Gillian
authors.initials: G
authors.lastname: Barratt
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000981:Antiprotozoal Agents / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002250:Carbon Radioisotopes; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008353:Mannitol / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D000074011:Peptide Transporter 1; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D027981:Symporters / Q000378:metabolism; D013696:Temperature; D013739:Testosterone / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D000981:Antiprotozoal Agents; D002250:Carbon Radioisotopes; D008565:Membrane Proteins; D000074011:Peptide Transporter 1; D027981:Symporters; D010767:Phosphorylcholine; D008353:Mannitol; D013739:Testosterone; C039128:miltefosine; D007770:L-Lactate Dehydrogenase