title: Transport of artemisinin and sodium artesunate in Caco-2 intestinal epithelial cells.
abstract: Artemisinin and its derivatives are becoming interesting alternatives to the commonly used antimalarial drugs because they are efficient in treating severe and multidrug resistant forms of Plasmodium falciparum malaria. A major drawback is the occurrence of recrudescence some time after treatment. Moderate oral bioavailability has been suggested as a possible cause. As one of the factors that might limit absorption after oral administration, we studied the intestinal permeability using an in vitro system of the intestinal mucosa, Caco-2. Concentrations of artemisinin were determined by UV after alkaline degradation, while for sodium artesunate, a capillary electrophoresis method was developed. Artemisinin easily crossed the epithelial cells by passive diffusion (Papp = 30.4 +/- 1.7 x 10(-6) cm s-1, pH 7.4). Permeability of the hemisuccinate analogue, sodium artesunate, was 8-fold lower (Papp = 4.0 +/- 0.4 x 10(-6) cm s-1 at pH 7.4) and strongly dependent on pH, which might result in site dependent resorption in an in vivo situation. Enzyme catalyzed ester hydrolysis of sodium artesunate in Caco-2 monolayers to the biologically active metabolite, dihydroartemisinin, was moderate. The results indicate that the transepithelial permeability is probably not a limiting factor in the overall absorption process after oral administration of artemisinin or sodium artesunate. Solubility, dissolution rate, stability, and first-pass metabolism are suggested as alternative limiting factors.
authors.affiliation: Laboratory of Galenical and Clinical Pharmacy, Catholic University Leuven, Onderwijs en Navorsing, Gasthuisberg, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Augustijns
authors.forename: A
authors.initials: A
authors.lastname: D'Hulst
authors.forename: J
authors.initials: J
authors.lastname: Van Daele
authors.forename: R
authors.initials: R
authors.lastname: Kinget
mesh_terms: D000962:Antimalarials / Q000493:pharmacokinetics*; D037621:Artemisinins; D000077332:Artesunate; D001692:Biological Transport; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007700:Kinetics; D012717:Sesquiterpenes / Q000493:pharmacokinetics*; D012995:Solubility
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D000077332:Artesunate; C031327:artemisinin