Division of Cellular and Molecular Medicine, Centre for Infection, St. George's University of London, London, United Kingdom.
Antimicrob Agents Chemother. 2011 Feb;55(2):550-6. doi: 10.1128/AAC.01216-10. Epub 2010 Dec 6.
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.
青蒿琥酯是临床试验中最有前途的青蒿素衍生物之一。以前使用放射性标记的青蒿素和双氢青蒿素的研究已经测量了疟原虫感染的红细胞中的摄取。在感染的红细胞中摄取量明显大于未感染的红细胞，但运输、结合和代谢对这一过程的相对贡献仍有待确定。在这项研究中，我们描述了 [(14)C]青蒿琥酯在体外进入未感染和疟原虫感染的人红细胞的机制。放射性标记的青蒿琥酯迅速进入未感染的红细胞，而不会超过细胞外浓度。未标记的青蒿琥酯在这个过程中没有竞争。放射性标记的青蒿琥酯通过时间和温度依赖的机制在感染的红细胞中被大量浓缩。未标记的青蒿琥酯可以阻断这种摄取。此外，还研究了青蒿琥酯进入三个亚细胞部分的摄取及其在这些部分中的分布，作为寄生虫成熟的函数。这些数据与理解这一类重要药物的作用机制有关。
