Artemisone uptake in Plasmodium falciparum-infected erythrocytes.
Artemisone is one of the most promising artemisinin derivatives in clinical trials. Previous studies with radiolabeled artemisinin and dihydroartemisinin have measured uptake in Plasmodium falciparum-infected erythrocytes. Uptake is much greater in infected than in uninfected erythrocytes, but the relative contributions of transport, binding, and metabolism to this process still await definition. In this study, we characterized mechanisms by which [(14)C]artemisone is taken up into uninfected and P. falciparum-infected human erythrocytes in vitro. Radiolabeled artemisone rapidly enters uninfected erythrocytes without much exceeding extracellular concentrations. Unlabeled artemisone does not compete in this process. Radiolabeled artemisone is concentrated greatly by a time- and temperature-dependent mechanism in infected erythrocytes. This uptake is abrogated by unlabeled artemisone. In addition, the uptake of artemisone into three subcellular fractions, and its distribution into these fractions, is examined as a function of parasite maturation. These data are relevant to an understanding of the mechanisms of action of this important class of drugs.
Division of Cellular and Molecular Medicine, Centre for Infection, St. George's University of London, London, United Kingdom.
Sophie
S
Pooley
Farrah A
FA
Fatih
Sanjeev
S
Krishna
Michael
M
Gerisch
Richard K
RK
Haynes
Ho-Ning
HN
Wong
Henry M
HM
Staines
D000962:Antimalarials / Q000378:metabolism*; D037621:Artemisinins / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism* / Q000469:parasitology*; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development*
D000962:Antimalarials; D037621:Artemisinins; D002250:Carbon Radioisotopes; C514498:artemisone