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.
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.
Authors: Luuk C T Dohmen; Adriana Navas; Deninson Alejandro Vargas; David J Gregory; Anke Kip; Thomas P C Dorlo; Maria Adelaida Gomez Journal: J Biol Chem Date: 2016-02-22 Impact factor: 5.157
Authors: A E Kip; H Rosing; M J X Hillebrand; M M Castro; M A Gomez; J H M Schellens; J H Beijnen; T P C Dorlo Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2015-06-24 Impact factor: 3.205
Authors: Anke E Kip; María Del Mar Castro; Maria Adelaida Gomez; Alexandra Cossio; Jan H M Schellens; Jos H Beijnen; Nancy Gore Saravia; Thomas P C Dorlo Journal: J Antimicrob Chemother Date: 2018-08-01 Impact factor: 5.790
Authors: Wei Zhang; Michael A Parniak; Stefan G Sarafianos; Philip E Empey; Lisa C Rohan Journal: Eur J Pharmacol Date: 2014-03-29 Impact factor: 4.432
Authors: Sara Botschuijver; Sophie A van Diest; Isabelle A M van Thiel; Rafael S Saia; Anne S Strik; Zhumei Yu; Daniele Maria-Ferreira; Olaf Welting; Daniel Keszthelyi; Gary Jennings; Sigrid E M Heinsbroek; Ronald P Oude Elferink; Frank H J Schuren; Wouter J de Jonge; René M van den Wijngaard Journal: Sci Rep Date: 2019-08-29 Impact factor: 4.379
Authors: Semra Palić; Anke E Kip; Jos H Beijnen; Jane Mbui; Ahmed Musa; Alexandra Solomos; Monique Wasunna; Joseph Olobo; Fabiana Alves; Thomas P C Dorlo Journal: J Antimicrob Chemother Date: 2020-11-01 Impact factor: 5.790