A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first-pass hepatic extraction
A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first-pass hepatic extraction
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DOI：
10.1111/j.1365-2125.2004.02321.x
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发表时间：
2005-02-01
影响因子：
3.4
通讯作者：
Ashton, M
中科院分区：
文献类型：
--
作者：
Gordi, T;Xie, RJ;Ashton, M
目的以前的研究表明，抗疟药青蒿素是一种有效的诱导剂，它本身的代谢在患者和健康受试者。本研究的目的是为了表征青蒿素在健康subjects.MethodsTwenty-four健康男性的时间依赖性药代动力学随机接受每日单剂量500毫克口服青蒿素5天，或单口服剂量100/100/250/250/500毫克的第一个5天。每组2例受试者在研究开始后的以下日期之一接受500 mg新剂量给药：第7、10、13、16、20或24天。采用高效液相色谱法测定第1、3、5天和最后一天采集的唾液样品中青蒿素的浓度。数据进行了分析，使用semiphysiological模型，将（a）autoinduction的前体代谢酶，和（B）一个两室药代动力学模型与一个单独的肝隔室，以模仿autoinduction和高肝extraction.ResultsArtemisinin的过程中发现，以诱导其自身的代谢与平均诱导时间为1.9小时，而酶消除半衰期估计为37.9小时。青蒿素的肝提取率估计为0.93，在代谢自诱导后增加到约0.99。该模型表明，自诱导主要影响生物利用度，但不影响全身清除率。AUC与剂量的非线性增加被解释为饱和的肝脏消除影响的首过extraction.ConclusionArtemisinin产生的酶诱导的快速发病，导致其自身的生物利用度随着时间的推移而下降。所提出的模型成功地描述了在接受两种不同剂量方案的化合物的健康受试者中代谢的自诱导的发作和正常化的时间过程。
AimsPrevious studies have shown that the antimalarial drug artemisinin is a potent inducer of its own metabolism in both patients and healthy subjects. The aim of this study was to characterize the time-dependent pharmacokinetics of artemisinin in healthy subjects.MethodsTwenty-four healthy males were randomized to receive either a daily single dose of 500 mg oral artemisinin for 5 days, or single oral doses of 100/100/250/250/500 mg on each of the first 5 days. Two subjects from each group were administered a new dose of 500 mg on one of the following days after the beginning of the study: 7, 10, 13, 16, 20, or 24. Artemisinin concentrations in saliva samples collected on days 1, 3, 5, and on the final day were determined by HPLC. Data were analysed using a semiphysiological model incorporating (a) autoinduction of a precursor to the metabolizing enzymes, and (b) a two-compartment pharmacokinetic model with a separate hepatic compartment to mimic the processes of autoinduction and high hepatic extraction.ResultsArtemisinin was found to induce its own metabolism with a mean induction time of 1.9 h, whereas the enzyme elimination half-life was estimated to 37.9 h. The hepatic extraction ratio of artemisinin was estimated to be 0.93, increasing to about 0.99 after autoinduction of metabolism. The model indicated that autoinduction mainly affected bioavailability, but not systemic clearance. Non-linear increases in AUC with dose were explained by saturable hepatic elimination affecting the first-pass extraction.ConclusionArtemisinin produces a rapid onset of enzyme induction, resulting in a decrease in its own bioavailability over time. The proposed model successfully described the time-course of the onset and normalization of the autoinduction of metabolism in healthy subjects receiving two different dosage regimens of the compound.