The role of bioactivation in the pharmacology and toxicology of the artemisinin-based antimalarials.

Artemisinin and artemisinin-based antimalarials are currently recommended as the frontline antimalarial treatment, with over 100 million courses administered annually. Despite possessing excellent therapeutic activity and tolerability, neurotoxicity and embryotoxicity have been reported in cross-species animal models. The endoperoxide group contained within the artemisinins is essential for pharmacologic and toxicological activity and it is hypothesized that its bioactivation to toxic C-centered radical species is the mechanistic basis for activity. The chemical nature of this activation and the ultimate toxic species remain controversial and this review will focus upon studies published on this topic over the past year. Furthermore, the possibility of chemical dissociation of pharmacology and toxicology in novel artemisinins will be discussed.