Navaratnam V, Mansor S M, Sit N W, Grace J, Li Q, Olliaro P
Centre for Drug Research, University Sains Malaysia, Penang.
Clin Pharmacokinet. 2000 Oct;39(4):255-70. doi: 10.2165/00003088-200039040-00002.
Various compounds of the artemisinin family are currently used for the treatment of patients with malaria worldwide. They are characterised by a short half-life and feature the most rapidly acting antimalarial drugs to date. They are increasingly being used, often in combination with other drugs, although our knowledge of their main pharmacological features (including their absorption, distribution, metabolism and excretion) is still incomplete. Such data are particularly important in the case of combinations. Artemisinin derivatives are converted primarily, but to different extents, to the bioactive metabolite artenimol after either parenteral or gastrointestinal administration. The rate of conversion is lowest for artelinic acid (designed to protect the molecule against metabolism) and highest for the water-soluble artesunate. The absolute and relative bioavailability of these compounds has been established in animals, but not in humans, with the exception of artesunate. Oral bioavailability in animals ranges, approximately, between 19 and 35%. A first-pass effect is highly probably for all compounds when administered orally. Artemisinin compounds bind selectively to malaria-infected erythrocytes to yet unidentified targets. They also bind modestly to human plasma proteins, ranging from 43% for artenimol to 81.5% for artelinic acid. Their mode of action is still not completely understood, although different theories have been proposed. The lipid-soluble artemether and artemotil are released slowly when administered intramuscularly because of the 'depot' effect related to the oil formulation. Understanding the pharmacokinetic profile of these 2 drugs helps us to explain the characteristics of the toxicity and neurotoxicity. The water-soluble artesunate is rapidly converted to artenimol at rates that vary with the route of administration, but the processes need to be characterised further, including the relative contribution of pH and enzymes in tissues, blood and liver. This paper intends to summarise contemporary knowledge of the pharmacokinetics of this class of compounds and highlight areas that need further research.
目前，青蒿素类的各种化合物在全球范围内用于治疗疟疾患者。它们的特点是半衰期短，是迄今为止起效最快的抗疟药物。它们越来越多地被使用，通常与其他药物联合使用，尽管我们对其主要药理学特性（包括吸收、分布、代谢和排泄）的了解仍不完整。在联合用药的情况下，这些数据尤为重要。青蒿素衍生物在肠胃外或胃肠道给药后，主要但程度不同地转化为生物活性代谢物青蒿琥酯。青蒿酸（旨在保护分子不被代谢）的转化率最低，水溶性青蒿琥酯的转化率最高。除青蒿琥酯外，这些化合物的绝对和相对生物利用度已在动物中确定，但尚未在人体中确定。动物口服生物利用度约在19%至35%之间。所有化合物口服给药时很可能存在首过效应。青蒿素化合物选择性地与感染疟疾的红细胞结合，靶点尚未明确。它们也与人类血浆蛋白有适度结合，从青蒿琥酯的43%到青蒿酸的81.5%不等。尽管已经提出了不同的理论，但其作用方式仍未完全了解。由于油剂配方的“储存”效应，脂溶性蒿甲醚和青蒿素肌内注射时释放缓慢。了解这两种药物的药代动力学特征有助于我们解释其毒性和神经毒性的特点。水溶性青蒿琥酯以随给药途径而变化的速率迅速转化为青蒿琥酯，但这些过程需要进一步表征，包括pH值和组织、血液及肝脏中酶的相对作用。本文旨在总结此类化合物药代动力学的当代知识，并突出需要进一步研究的领域。
