Stability of the antimalarial drug dihydroartemisinin under physiologically relevant conditions: implications for clinical treatment and pharmacokinetic and in vitro assays.
Artemisinins are peroxidic antimalarial drugs known to be very potent but highly chemically unstable; they degrade in the presence of ferrous iron, Fe(II)-heme, or biological reductants. Less documented is how this translates into chemical stability and antimalarial activity across a range of conditions applying to in vitro testing and clinical situations. Dihydroartemisinin (DHA) is studied here because it is an antimalarial drug on its own and the main metabolite of other artemisinins. The behaviors of DHA in phosphate-buffered saline, plasma, or erythrocyte lysate at different temperatures and pH ranges were examined. The antimalarial activity of the residual drug was evaluated using the chemosensitivity assay on Plasmodium falciparum, and the extent of decomposition of DHA was established through use of high-performance liquid chromatography with electrochemical detection analysis. The role of the Fe(II)-heme was investigated by blocking its reactivity using carbon monoxide (CO). A significant reduction in the antimalarial activity of DHA was seen after incubation in plasma and to a lesser extent in erythrocyte lysate. Activity was reduced by half after 3 h and almost completely abolished after 24 h. Serum-enriched media also affected DHA activity. Effects were temperature and pH dependent and paralleled the increased rate of decomposition of DHA from pH 7 upwards and in plasma. These results suggest that particular care should be taken in conducting and interpreting in vitro studies, prone as their results are to experimental and drug storage conditions. Disorders such as fever, hemolysis, or acidosis associated with malaria severity may contribute to artemisinin instability and reduce their clinical efficacy.
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy.
Silvia
S
Parapini
UNICEF/UNDP/World Bank/WHO Special Programme on Research & Training in Tropical Diseases (TDR), World Health Organization, Geneva, Switzerland Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Piero
P
Olliaro
Centre for Drug Research, Universiti Sains Malaysia, Penang, Malaysia Postgraduate, Research and Strategic Development, Taylor's University, Selangor, Malaysia.
Visweswaran
V
Navaratnam
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy.
Donatella
D
Taramelli
Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università di Milano, Milan, Italy nicoletta.basilico@unimi.it.
Nicoletta
N
Basilico
D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D037621:Artemisinins / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001205:Ascorbic Acid / Q000737:chemistry; D002248:Carbon Monoxide / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D055664:Electrochemical Techniques; D004912:Erythrocytes / Q000737:chemistry / Q000378:metabolism; D006207:Half-Life; D006418:Heme / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D010963:Plasmodium falciparum / Q000187:drug effects; D013696:Temperature
D000962:Antimalarials; D037621:Artemisinins; D006418:Heme; C039060:artenimol; D002248:Carbon Monoxide; D001205:Ascorbic Acid