Pukrittayakamee S, Looareesuwan S, Keeratithakul D, Davis T M, Teja-Isavadharm P, Nagachinta B, Weber A, Smith A L, Kyle D, White N J
Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Eur J Clin Pharmacol. 1997;52(6):487-93. doi: 10.1007/s002280050323.
To assess the factors that contribute to impaired quinine clearance in acute falciparum malaria.
Sixteen adult Thai patients with severe or moderately severe falciparum malaria were studied, and 12 were re-studied during convalescence.
The clearance of quinine, dihydroquinine (an impurity comprising up to 10% of commercial quinine formulations), antipyrine (a measure of hepatic mixed-function oxidase activity), indocyanine green (ICG) (a measure of liver blood flow), and iothalamate (a measure of glomerular filtration rate) were measured simultaneously, and the relationship of these values to the biotransformation of quinine to the active metabolite 3-hydroxyquinine was assessed.
During acute malaria infection, the systemic clearance of quinine, antipyrine and ICG and the biotransformation of quinine to 3-hydroxyquinine were all reduced significantly when compared with values during convalescence. Iothalamate clearance was not affected significantly and did not correlate with the clearance of any of the other compounds. The clearance of total and free quinine correlated significantly with antipyrine clearance (rs = 0.70, P = 0.005 and rs = 0.67, P = 0.013, respectively), but not with ICG clearance (rs = 0.39 and 0.43 respectively, P > 0.15). In a multiple regression model, antipyrine clearance and plasma protein binding accounted for 71% of the variance in total quinine clearance in acute malaria. The pharmacokinetic properties of dihydroquinine were generally similar to those of quinine, although dihydroquinine clearance was less affected by acute malaria. The mean ratio of quinine to 3-hydroxyquinine area under the plasma concentration-time curve (AUC) values in acute malaria was 12.03 compared with 6.92 during convalescence P = 0.01. The mean plasma protein binding of 3-hydroxyquinine was 46%, which was significantly lower than that of quinine (90.5%) or dihydroquinine (90.5%).
The reduction in quinine clearance in acute malaria results predominantly from a disease-induced dysfunction in hepatic mixed-function oxidase activity (principally CYP 3A) which impairs the conversion of quinine to its major metabolite, 3-hydroxyquinine. The metabolite contributes approximately 5% of the antimalarial activity of the parent compound in malaria, but up to 10% during convalescence.
评估导致急性恶性疟原虫疟疾中奎宁清除受损的因素。
对16例患有重度或中度重度恶性疟原虫疟疾的成年泰国患者进行了研究，其中12例在康复期进行了再次研究。
同时测量奎宁、二氢奎宁（一种杂质，在商业奎宁制剂中含量高达10%）、安替比林（肝混合功能氧化酶活性的一种测量指标）、吲哚菁绿（ICG）（肝血流量的一种测量指标）和碘他拉酸盐（肾小球滤过率的一种测量指标）的清除率，并评估这些值与奎宁向活性代谢物3-羟基奎宁生物转化的关系。
与康复期的值相比，急性疟疾感染期间，奎宁、安替比林和ICG的全身清除率以及奎宁向3-羟基奎宁的生物转化均显著降低。碘他拉酸盐清除率未受到显著影响，且与其他任何化合物的清除率均无相关性。总奎宁和游离奎宁的清除率与安替比林清除率显著相关（rs分别为0.70，P = 0.005和rs为0.67，P = 0.013），但与ICG清除率无关（rs分别为0.39和0.43，P > 0.15）。在多元回归模型中，安替比林清除率和血浆蛋白结合占急性疟疾中总奎宁清除率变异的71%。二氢奎宁的药代动力学特性通常与奎宁相似，尽管二氢奎宁清除率受急性疟疾的影响较小。急性疟疾中血浆浓度-时间曲线（AUC）值的奎宁与3-羟基奎宁的平均比值为12.03，而康复期为6.92（P = 0.01）。3-羟基奎宁的平均血浆蛋白结合率为46%，显著低于奎宁（90.5%）或二氢奎宁（90.5%）。
急性疟疾中奎宁清除率的降低主要源于疾病诱导的肝混合功能氧化酶活性（主要是CYP 3A）功能障碍，这损害了奎宁向其主要代谢物3-羟基奎宁的转化。该代谢物在疟疾中对母体化合物抗疟活性的贡献约为5%，但在康复期可达10%。
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