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Intestinal Absorption of Miltefosine: Contribution of Passive Paracellular Transport

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Abstract

Purpose

This study aimed to characterize the transepithelial transport of miltefosine (HePC), the first orally effective drug against visceral leishmaniasis, across the intestinal barrier to further understand its oral absorption mechanism.

Materials and Methods

Caco-2 cell monolayers were used as an in vitro model of the human intestinal barrier. The roles of active and passive mechanisms in HePC intestinal transport were investigated and the relative contributions of the transcellular and paracellular routes were estimated.

Results

HePC transport was observed to be pH-independent, partially temperature-dependent, linear as a function of time and non-saturable as a function of concentration. The magnitude of HePC transport was quite similar to that of the paracellular marker mannitol, and EDTA treatment led to an increase in HePC transport. Furthermore, HePC transport was found to be similar in the apical-to-basolateral and basolateral-to-apical directions, strongly suggesting that HePC exhibits non-polarized transport and that no MDR-mediated efflux was involved.

Conclusions

These results demonstrate that HePC crosses the intestinal epithelium by a non-specific passive pathway and provide evidence supporting a concentration-dependent paracellular transport mechanism, although some transcellular diffusion cannot be ruled out. Considering that HePC opens epithelial tight junctions, this study shows that HePC may promote its own permeation across the intestinal barrier.

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Abbreviations

AP:

apical

APC:

alkylphosphocholine

BL:

basolateral

HePC:

hexadecylphosphocholine (miltefosine)

P app :

apparent permeability coefficient

P-gp:

P-glycoprotein

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Acknowledgment

The authors gratefully acknowledge Hélène Chacun for valuable help with radioactivity studies.

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Authors and Affiliations

  1. Laboratoire de Physico-chimie, Pharmacotechnie et Biopharmacie, UMR CNRS 8612, IFR 141, University Paris-Sud 11, Faculté de Pharmacie, 5 rue J.B. Clément, Châtenay-Malabry Cedex, F-92296, France

    Cécile Ménez & Gillian Barratt

  2. Laboratoire de Pharmacie Clinique UPRES 2706, IFR 141, University Paris-Sud 11, Faculté de Pharmacie, 5 rue J.B. Clément, Châtenay-Malabry Cedex, F-92296, France

    Marion Buyse & Robert Farinotti

  3. Département d’Ingénierie et d’Etudes des Protéines (DIEP), CEA, Bâtiment 152, CEA/Saclay, Gif-sur-Yvette, F-91191, France

    Christophe Dugave

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  1. Cécile Ménez
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  2. Marion Buyse
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  3. Christophe Dugave
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  4. Robert Farinotti
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  5. Gillian Barratt
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Correspondence to Gillian Barratt.

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Ménez, C., Buyse, M., Dugave, C. et al. Intestinal Absorption of Miltefosine: Contribution of Passive Paracellular Transport. Pharm Res 24, 546–554 (2007). https://doi.org/10.1007/s11095-006-9170-7

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  • DOI: https://doi.org/10.1007/s11095-006-9170-7

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