Pharmacokinetic and Toxicological Profile of Artemisinin Compounds: An Update

Abstract

Artemisinin has been used effectively in malaria treatment. With the emerging resistance to malaria, the optimum and judicial use of the drug has become important. The drug metabolism and toxicology can have an impact on the therapeutic profile and clinical use of this antimalarial agent. In this review, we discuss the pharmacokinetics and toxicological aspects of artemisinin and its therapeutic implications. Artemisinins have several dosing routes including oral, intramuscular, intravenous and rectal. With repeated dosing, artemisinin has propensity for autoinduction, leading to decreased plasma levels on repeated dosing. Combination with other antimalarials in most cases did not influence the pharmacokinetics of artemisinins. Interactions with cytochrome P₄₅₀ inhibitors are known but these neither affect the efficacy nor the toxicity of the respective derivative. Artemisinins are generally regarded to be of low toxicity. Two major problems associated with them are neurotoxicity and reproductive toxicity. But the extent of this neurotoxicity is dependent on the nature of the compound, on the route of administration, and on the nature of the formulation. Moreover, it occurs in humans at very high doses. However, as a matter of precaution, the use of artemisinins in the first trimester of pregnancy has been contraindicated.

Artesunate Tolerance in Transgenic Plasmodium falciparum Parasites Overexpressing a Tryptophan-Rich Protein

“…The doses used were in the range of plasma concentrations observed in vivo within 3 h after drug administration (9,38,46), knowing that the actual levels of active drug are difficult to assess given the rapid degradation of artesunate into dihydro artemisinin both in vivo (36) and in vitro (3,23). Under these conditions, a dose-dependent increase in PArt protein was observed under artesunate pressure.…”

Alternatives to currently used antimalarial drugs: in search of a magic bullet

“…A Phase II interventional study testing artemisone for treating uncomplicated P. falciparum malaria planned for Western Cambodia (NCT00936767) has been withdrawn for unknown reasons. Some studies reported neurological and auditory side effects such as ataxia and slurred speech [42, 43] due to ACTs. However, no strong evidence exists to confirm neurological side effects.…”

Therapeutic and Toxicological Inhibition of Vasculogenesis and Angiogenesis Mediated by Artesunate, a Compound with Both Antimalarial and Anticancer Efficacy

“…DHA has been shown in rat whole embryo cultures to primarily affect primitive red blood cells causing subsequent tissue damage and dysmorphogenesis. AS has also been found to be embryolethal and teratogenic in rats, suggesting that embryonic erythroblasts are the primary target of AS toxicity in the rat embryo after in vivo treatment, preceding embryolethality and organ malformations (Medhi et al, 2009). In particular, cancer angiogenesis plays a key role in the growth, invasion, and metastasis of tumors.…”