Modulation of intestinal barrier properties by miltefosine.Biochem Pharmacol. 2006 Feb 14; 71(4):486-96.BP
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.