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Antimicrobial Agents and Chemotherapy, November 2006, p. 3793-3800, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00837-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Interaction between Miltefosine and Amphotericin B: Consequences for Their Activities towards Intestinal Epithelial Cells and Leishmania donovani Promastigotes In Vitro

Laboratoire de Physico-chimie, Pharmacotechnie et Biopharmacie, UMR CNRS 8612, Univ. Paris-Sud 11, Faculté de Pharmacie, IFR 141, Châtenay-Malabry F-92296, France,¹ Laboratoire de Pharmacie Clinique, UPRES 2706, Univ. Paris-Sud 11, Faculté de Pharmacie, IFR 141, Châtenay-Malabry F-92296, France,² Chimiothérapie antiparasitaire, UMR CNRS 8076, Univ. Paris-Sud 11, Faculté de Pharmacie, IFR 141, Châtenay-Malabry F-92296, France³

Received 10 July 2006/ Returned for modification 20 August 2006/ Accepted 1 September 2006

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 µM, 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.

Published ahead of print on 11 September 2006.