Intestinal absorption of miltefosine: contribution of passive paracellular transport.
OBJECTIVE
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.


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.
Ménez
Cécile
C
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.
Buyse
Marion
M
Dugave
Christophe
C
Farinotti
Robert
R
Barratt
Gillian
G
D000981:Antiprotozoal Agents / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002250:Carbon Radioisotopes; D002463:Cell Membrane Permeability / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D004058:Diffusion; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D008353:Mannitol / Q000493:pharmacokinetics; D008954:Models, Biological; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013696:Temperature; D013739:Testosterone / Q000493:pharmacokinetics; D019108:Tight Junctions / Q000378:metabolism; D013997:Time Factors
D000981:Antiprotozoal Agents; D002250:Carbon Radioisotopes; D002614:Chelating Agents; D010767:Phosphorylcholine; D008353:Mannitol; D013739:Testosterone; C039128:miltefosine; D004492:Edetic Acid