title: Interaction between miltefosine and amphotericin B: consequences for their activities towards intestinal epithelial cells and Leishmania donovani promastigotes in vitro.
abstract: The aim of this study was to evaluate the potential of a combination of two antileishmanial drugs, miltefosine (HePC) and amphotericin B (AMB), when administered by the oral route. Caco-2 cell monolayers were used as a validated in vitro model of the intestinal barrier and Leishmania donovani promastigotes as a model for evaluating the effect of the drug combination. Spectroscopic measurements demonstrated that HePC and AMB associate, leading to the formation of mixed aggregates in which AMB is solubilized as monomers. The incubation of the association of HePC and AMB with Caco-2 cell monolayers, at a concentration higher than 5 microM, led to (i) a reduction of the HePC-induced paracellular permeability enhancement in Caco-2 cell monolayers, (ii) an inhibition of the uptake of both drugs, and (iii) a decrease in the transepithelial transport of both drugs, suggesting that a pharmacokinetic antagonism between HePC and AMB could occur after their oral administration. However, the combination did not exhibit any antagonism or synergy in its antileishmanial activity. These results demonstrated a strong physicochemical interaction between HePC and AMB, depending on the concentration of each, which could have important consequences for their biological activities, if they are administered together.
authors.affiliation: Faculty of Pharmacy, University of Paris-Sud, Laboratoire de Physico-chimie, Pharmacotechnie et Biopharmacie, UMR CNRS 8612, Tour D5, 2ème étage, 5 rue J.B. Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Ménez
authors.forename: Marion
authors.initials: M
authors.lastname: Buyse
authors.forename: Madeleine
authors.initials: M
authors.lastname: Besnard
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Loiseau
authors.forename: Gillian
authors.initials: G
authors.lastname: Barratt
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D004347:Drug Interactions; D004847:Epithelial Cells / Q000187:drug effects*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects*; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000981:Antiprotozoal Agents; D010767:Phosphorylcholine; C039128:miltefosine; D000666:Amphotericin B