Artemisinin permeability via Caco-2 cells increases after simulated digestion of Artemisia annua leaves

Abstract Ethnopharmacological relevance Artemisia annua has been used for > 2000 yrs to treat fever and is more recently known for producing the important antimalarial drug, artemisinin. Aim of the study Artemisinin combination therapies (ACTs) are effective for treating malaria, but are often unavailable to those in need. Dried leaves of A. annua (DLA) have recently been studied as a cost effective alternative to traditional ACTs. DLA was shown to dramatically increase oral bioavailability compared to pure artemisinin, so more investigation into the mechanisms causing this increased bioavailability is needed. Materials and methods In this study, we used a simulated digestion system coupled with Caco-2 cell permeability assays to investigate the intestinal permeability of DLA compared to pure artemisinin. We also determined the effects of different phytochemicals (7 flavonoids, 3 monoterpenes, 2 phenolic acids, scopoletin and inulin) and the cytochrome P450 isoform CYP3A4 on artemisinin intestinal permeability. Results Artemisinin permeability, when delivered as digested DLA, significantly increased by 37% (P app = 8.03 × 10 −5  cm s −1 ) compared to pure artemisinin (P app = 5.03 × 10 −5  cm s −1 ). However, none of the phytochemicals tested or CYP3A4 had any significant effect on the intestinal permeability of artemisinin. We also showed that essential oil derived from A. annua negatively affected the intestinal permeability of artemisinin, but only after simulated digestion. Finally, we showed that A. annua essential oil reduced the transepithelial electrical resistance of Caco-2 monolayers, but only in the presence of bile. Although also reduced by essential oils, artemisinin P app subsequently recovered in the presence of plant matrix. Conclusions These results shed light on the mechanisms by which DLA enhances the oral bioavailability of artemisinin.