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首页> 美国卫生研究院文献>Antimicrobial Agents and Chemotherapy >Validation and Pharmacokinetic Application of a High-Performance Liquid Chromatographic Technique for Determining the Concentrations of Amodiaquine and Its Metabolite in Plasma of Patients Treated with Oral Fixed-Dose Amodiaquine-Artesunate Combination in Areas of Malaria Endemicity
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Validation and Pharmacokinetic Application of a High-Performance Liquid Chromatographic Technique for Determining the Concentrations of Amodiaquine and Its Metabolite in Plasma of Patients Treated with Oral Fixed-Dose Amodiaquine-Artesunate Combination in Areas of Malaria Endemicity

机译：高效液相色谱法测定疟疾流行地区口服固定剂量氨二喹-青蒿琥酯联合治疗患者血浆中阿莫地喹及其代谢物的含量及其有效性

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Artemisinin-based combination therapies (ACTs) have been adopted by most African countries, including Nigeria, as first-line treatments for uncomplicated falciparum malaria. Fixed-dose combinations of these ACTs, amodiaquine-artesunate (FDC AQAS) and artemether-lumefantrine (AL), were introduced in Nigeria to improve compliance and achieve positive outcomes of malaria treatment. In order to achieve clinical success with AQAS, we developed and validated a simple and sensitive high-performance liquid chromatography (HPLC) method with UV detection for determination of amodiaquine (AQ) and desethylamodiaquine (DAQ) in plasma using liquid-liquid extraction of the drugs with diethyl ether following protein precipitation with acetonitrile. Chromatographic separation was achieved using an Agilent Zorbax C18 column and a mobile phase consisting of distilled water-methanol (80:20 [vol/vol]) with 2% (vol/vol) triethylamine, pH 2.2, at a flow rate of 1 ml/min. Calibration curves in spiked plasma were linear from 100 to 1,000 ng/ml (r > 0.99) for both AQ and DAQ. The limit of detection was 1 ng (sample size, 20 μl). The intra- and interday coefficients of variation at 150, 300, and 900 ng/ml ranged from 1.3 to 4.8%, and the biases were between 6.4 and 9.5%. The mean extraction recoveries of AQ and DAQ were 80.0% and 68.9%, respectively. The results for the pharmacokinetic parameters of DAQ following oral administration of FDC AQAS (612/200 mg) for 3 days in female and male patients with uncomplicated falciparum malaria showed that the maximum plasma concentrations (Cmax) (740 ± 197 versus 767 ± 185 ng/ml), areas under the plasma concentration-time curve (AUC) (185,080 ± 20,813 versus 184,940 ± 16,370 h · ng/ml), and elimination half-life values (T1/2) (212 ± 1.14 versus 214 ± 0.84 h) were similar (P > 0.05).
机译：基于青蒿素的联合疗法（ACTs）已被包括尼日利亚在内的大多数非洲国家采用，作为治疗非复杂性恶性疟疾的一线疗法。在尼日利亚引进了这些ACT的固定剂量组合，即阿莫地喹-青蒿琥酯（FDC AQAS）和蒿甲醚-卢美他汀（AL），以提高依从性并实现疟疾治疗的积极成果。为了在AQAS上取得临床成功，我们开发并验证了一种简单而灵敏的高效液相色谱（HPLC）方法，该方法具有UV检测功能，可通过液-液萃取法测定血浆中的阿莫地喹（AQ）和去甲乙二酰胺（DAQ）。用乙腈沉淀蛋白质后，将药物与乙醚混合。使用Agilent Zorbax C18色谱柱和流动相，由蒸馏水-甲醇（80:20 [vol / vol]）和2％（vol / vol）三乙胺，pH 2.2，以1 ml的流速进行色谱分离/分钟。对于AQ和DAQ，加标血浆中的校准曲线从100到1,000 ng / ml呈线性（r> 0.99）。检测限为1 ng（样品量为20μl）。 150、300和900 ng / ml的日内和日间变异系数在1.3％至4.8％之间，偏差在6.4％至9.5％之间。 AQ和DAQ的平均提取回收率分别为80.0％和68.9％。在患有单纯性恶性疟疾的女性和男性患者中口服FDC AQAS（612/200 mg）3天后，DAQ的药代动力学参数结果显示最大血浆浓度（Cmax）（740±197对767±185 ng） / ml），血浆浓度-时间曲线（AUC）下的面积（185,080±20,813对184,940±16,370 h·ng / ml）和消除半衰期值（T1 / 2）（212±1.14对214±0.84 h ）相似（P> 0.05）。

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