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Stability of the antimalarial drug dihydroartemisinin under physiologically relevant conditions: implications for clinical treatment and pharmacokinetic and in vitro assays.

Abstract：

: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.

journal_name

Antimicrob Agents Chemother

journal_title

Antimicrobial agents and chemotherapy

authors

Parapini S,Olliaro P,Navaratnam V,Taramelli D,Basilico N

doi

10.1128/AAC.00183-15

subject

Has Abstract

pub_date

2015-07-01 00:00:00

pages

4046-52

issue

eissn

0066-4804

issn

1098-6596

pii

AAC.00183-15

journal_volume

pub_type

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Stability of the antimalarial drug dihydroartemisinin under physiologically relevant conditions: implications for clinical treatment and pharmacokinetic and in vitro assays.