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 ( P app  = 30.4 ± 1.7 × 10 −6 cm s −1 , pH 7.4). Permeability of the hemisuccinate analogue, sodium artesunate, was 8-fold lower ( P app  = 4.0 ± 0.4 × 10 −6 cm s −1 at pH 7.4) and strongle 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 monolayer to the biologically active metabolite, dihrdroatremisinin, was moderate. The results indicate overall absorption process after oral administration of artemisinin of sodium artesunate. Solubility, Dissolution rate, stabilit, and first-pass metabolism are suggested as alternative limiting factors.