White N J
Clin Pharmacokinet. 1985 May-Jun;10(3):187-215. doi: 10.2165/00003088-198510030-00001.
For the past 300 years antimalarial dosage regimens have not been based on pharmacokinetic information. However, now that this information is available, it is appropriate to examine current recommendations for prophylaxis and treatment. In healthy subjects, the cinchona alkaloids (quinine and quinidine), primaquine and proguanil (chloroguanide) are all rapidly eliminated with half-lives (t1/2 beta) of between 6 and 12 hours. Hepatic biotransformation accounts for approximately 80, 96 and 50% of their total clearance, respectively. In malaria, the pharmacokinetic properties of quinine and quinidine are significantly altered with a decrease in the apparent volume of distribution (Vd), prolongation of the elimination half-life, and a reduction in systemic clearance (CL) that is proportional to the severity of infection. Red cell concentrations and plasma protein binding are both increased in severe disease. Parenteral quinine or quinidine should be given by slow intravenous infusion rather than by intravenous or intramuscular injection, and a loading dose is necessary in severe infections. Chloroquine (t1/2 beta 6 to 50 days) and mefloquine (t1/2 beta 6.5 to 33 days) have extensive tissue distribution and prolonged activity after a single dose. Both drugs are concentrated in erythrocytes and 55% of chloroquine and 98% of mefloquine in plasma is bound to protein. The pharmacokinetics of chloroquine are complex and, because of the extremely long beta phase, difficult to accurately define. Pyrimethamine (t1/2 35 to 175 hours) has more limited tissue distribution, plasma and erythrocyte concentrations are similar, and 85% of the drug in plasma is bound to plasma proteins. The clearance of quinine, mefloquine and pyrimethamine appears to be higher in children than in adults. Currently, most of the information available on disposition of antimalarial drugs in humans is derived from studies in healthy adult subjects. More information is required on their pharmacokinetics in malaria, pregnancy, and in young children.
在过去的300年里，抗疟药物的给药方案并非基于药代动力学信息。然而，既然现在已有了这些信息，就应当审视当前关于预防和治疗的建议。在健康受试者中，金鸡纳生物碱（奎宁和奎尼丁）、伯氨喹和氯胍（氯喹胍）的消除都很快，半衰期（t1/2β）在6至12小时之间。肝脏生物转化分别占其总清除率的约80%、96%和50%。在疟疾患者中，奎宁和奎尼丁的药代动力学特性会发生显著改变，表现为表观分布容积（Vd）减小、消除半衰期延长以及全身清除率（CL）降低，且降低程度与感染严重程度成正比。在重症疾病中，红细胞浓度和血浆蛋白结合率均会升高。静脉注射奎宁或奎尼丁时应采用缓慢静脉输注而非静脉推注或肌肉注射，重症感染时需要给予负荷剂量。氯喹（t1/2β为6至50天）和甲氟喹（t1/2β为6.5至33天）单次给药后在组织中的分布广泛且活性持久。这两种药物均在红细胞中浓集，血浆中55%的氯喹和98%的甲氟喹与蛋白结合。氯喹的药代动力学较为复杂，由于β相极长，难以准确界定。乙胺嘧啶（t1/2为35至175小时）的组织分布较局限，血浆和红细胞浓度相似，血浆中85%的药物与血浆蛋白结合。奎宁、甲氟喹和乙胺嘧啶在儿童中的清除率似乎高于成人。目前，关于抗疟药物在人体内处置的大部分现有信息来自对健康成年受试者的研究。对于它们在疟疾、妊娠及幼儿中的药代动力学，还需要更多信息。
