Pharmacokinetics of artemisinin-type compounds

Various compounds of the artemisinin family are currently used for the trea tment of patients with malaria worldwide. They are characterised by a short half-life and feature the most rapidly acting antimalarial drugs to date. They are increasingly being used, often in combination with other drugs, al though our knowledge of their main pharmacological features (including thei r absorption, distribution, metabolism and excretion) is still incomplete. Such data are particularly important in the case of combinations. Artemisin in derivatives are converted primarily, but to different extents, to the bi oactive metabolite artenimol after either parenteral or gastrointestinal ad ministration. The rate of conversion is lowest for artelinic acid (designed to protect the molecule against metabolism) and highest for the water-solu ble artesunate, The absolute and relative bioavailability of these compound s has been established in animals, but not in humans, with the exception of artesunate. Oral bioavailability in animals ranges, approximately, between 19 and 35%. A first-pass effect is highly probably fur all compounds when administered orally. Artemisinin compounds bind selectively to malaria-infe cted erythrocytes to yet unidentified targets. They also bind modestly to h uman plasma proteins, ranging from 43% for artenimol to 81.5% for artelinic acid. Their mode of action is still not completely understood, although different theories have been proposed. The lipid-soluble artemether and artemotil ar e released slowly when administered intramuscularly because of the 'depot' effect related to the oil formulation. Understanding the pharmacokinetic pr ofile of these 2 drugs helps us to explain the characteristics of the toxic ity and neurotoxicity. The water-soluble artesunate is rapidly converted to artenimol at rates that vary with the route of administration, but the pro cesses need to be characterised further, including the relative contributio n of pH and enzymes in tissues, blood and liver. This paper intends to summ arise contemporary knowledge of the pharmacokinetics of this class of compo unds and highlight areas that need further research.