Gil J P, Gil Berglund E
Karolinska Institute, Malaria Research Unit, Division of Infectious Diseases, Department of Medicine, Karolinska University Hospital, M9:02, KS 17176 Stockholm, Sweden.
Pharmacogenomics. 2007 Feb;8(2):187-98. doi: 10.2217/14622416.8.2.187.
Malaria is a major infectious disease. In the last 10 years it has killed more than 20 million people, mainly small children in Africa. The highly efficacious artemisinine combination therapy is being launched globally, constituting the main hope for fighting the disease. Amodiaquine is a main partner in these combinations. Amodiaquine is almost entirely metabolized by the polymorphic cytochrome P450 (CYP) isoform 2C8 to the pharmacologically active desethylamodiaquine. The question remains whether the efficacy of amodiaquine is affected by the gene polymorphism. Genotype-inferred low metabolizers are found in 1-4% of African populations, which corresponds to millions of expected exposures to the drug. In vivo pharmacokinetic data on amodiaquine is limited. By combining it with published in vitro pharmacodynamic and drug metabolism information, we review and predict the possible relevance, or lack of, of CYP2C8 polymorphisms in the present and future efficacy of amodiaquine. Chloroquine and dapsone, both substrates of CYP2C8, are also discussed in the same context.
疟疾是一种主要的传染病。在过去10年里，它已导致超过2000万人死亡，主要是非洲的幼儿。高效的青蒿素联合疗法正在全球推出，这是抗击该疾病的主要希望。阿莫地喹是这些联合疗法中的主要药物。阿莫地喹几乎完全由多态性细胞色素P450（CYP）同工酶2C8代谢为具有药理活性的去乙基阿莫地喹。阿莫地喹的疗效是否受基因多态性影响仍是个问题。在1%至4%的非洲人群中发现了基因型推断的低代谢者，这相当于数百万次预期的药物暴露。关于阿莫地喹的体内药代动力学数据有限。通过将其与已发表的体外药效学和药物代谢信息相结合，我们回顾并预测了CYP2C8多态性对阿莫地喹当前和未来疗效可能具有或不具有的相关性。氯喹和氨苯砜都是CYP2C8的底物，也在相同背景下进行了讨论。
