Preliminary assessment of the effect of antimalarial herbal extracts on the metabolism of artesunate to active dihydroartemisinin

Due to the resistance of Plasmodium falciparum malaria to a number of antimalarial drugs, the WHO has recommended artemisinin-based combination therapy (ACT) since 2001. Artemisinin, the primary drug, is insoluble in water and has poor bioavailability limiting its effectiveness. Its semi-synthetic derivative, artesunate, is water-soluble and therefore available for oral and parenteral administration. The antimalarial activity of the artemisinin derivatives depends on their active metabolite, dihydroartemisinin which is formed through the enzymatic activity of CYP2A6, CYP2B6 and CYP3A4. Any inhibitory activity on this enzymatic process may lead to sub-therapeutic exposure to the active metabolite presenting the risk of the parasite developing resistance to artemisinins. Antimalarial herbal preparations are common complementary medicines often consumed concomitantly with the ACTs especially in West Africa. Seven of these herbal products were identified and their extracts incubated with artesunate in human liver microsomes. The metabolism of artesunate and the generation of dihydroartemisinin were monitored in the presence and absence of the herbal extracts. Five of the herbs – Tithonia diversifolia, Kalanchoe pinnata, Mangifera indica, Phyllanthus amarus, and Annona muricata- caused significant inhibition (> 70%) of the metabolism of artesunate, and similar magnitude of inhibition of dihydroartemisinin generation. This results suggest the likelihood of herb-artesunate interaction with the attendant risk of sub-therapeutic exposure to dihydroartemisin and resistance development, warrent further studies.