Krishna S, White N J
Department of Cellular and Molecular Sciences, St George's Hospital Medical School, London, England.
Clin Pharmacokinet. 1996 Apr;30(4):263-99. doi: 10.2165/00003088-199630040-00002.
Malaria is associated with a reduction in the systemic clearance and apparent volume of distribution of the cinchona alkaloids; this reduction is proportional to the disease severity. There is increased plasma protein binding, predominantly to alpha 1-acid glycoprotein, and elimination half-lives (in healthy adults quinine t1/2z = 11 hours, quinidine t1/2z = 8 hours) are prolonged by 50%. Systemic clearance is predominantly by hepatic biotransformation to more polar metabolites (quinine 80%, quinidine 65%) and the remaining drug is eliminated unchanged by the kidney. Quinine is well absorbed by mouth or following intramuscular injection even in severe cases of malaria (estimated bioavailability more than 85%). Quinine and chloroquine may cause potentially lethal hypotension if given by intravenous injection. Chloroquine is extensively distributed with an enormous total apparent volume of distribution (Vd) more than 100 L/kg, and a terminal elimination half-life of 1 to 2 months. As a consequence, distribution rather than elimination processes determine the blood concentration profile of chloroquine in patients with acute malaria. Parenteral chloroquine should be given either by continuous intravenous infusion, or by frequent intramuscular or subcutaneous injections of relatively small doses. Oral bioavailability exceeds 75%. Amodiaquine is a pro-drug for the active antimalarial metabolite desethylamodiaquine. Its pharmacokinetic properties are similar to these of chloroquine although the Vd is smaller (17 to 34 L/kg) and the terminal elimination half-life is 1 to 3 weeks.
疟疾与金鸡纳生物碱的全身清除率降低及表观分布容积减小有关；这种降低与疾病严重程度成正比。血浆蛋白结合增加，主要是与α1-酸性糖蛋白结合，消除半衰期（健康成年人中奎宁t1/2z = 11小时，奎尼丁t1/2z = 8小时）延长50%。全身清除主要通过肝脏生物转化为极性更强的代谢产物（奎宁为80%，奎尼丁为65%），其余药物经肾脏原形排出。即使在重症疟疾病例中，奎宁口服或肌内注射后吸收良好（估计生物利用度超过85%）。如果静脉注射，奎宁和氯喹可能会引起潜在致命的低血压。氯喹分布广泛，总表观分布容积极大（超过100 L/kg），终末消除半衰期为1至2个月。因此，在急性疟疾患者中，氯喹的血药浓度曲线由分布而非消除过程决定。肠外给予氯喹应采用持续静脉输注，或频繁肌内或皮下注射相对小剂量。口服生物利用度超过75%。阿莫地喹是活性抗疟代谢产物去乙基阿莫地喹的前体药物。其药代动力学特性与氯喹相似，尽管表观分布容积较小（17至34 L/kg），终末消除半衰期为1至3周。
