Characterisation of the human liver in vitro metabolic pattern of artemisinin and auto-induction in the rat by use of nonlinear mixed effects modelling
Characterisation of the human liver in vitro metabolic pattern of artemisinin and auto-induction in the rat by use of nonlinear mixed effects modelling
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DOI：
10.1002/bdd.342
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发表时间：
2003-03-01
影响因子：
2.1
通讯作者：
Ashton, M
中科院分区：
文献类型：
--
作者：
Svensson, USH;Mäki-Jouppila, M;Ashton, M
目的：本研究的目的是表征人类和大鼠肝微粒体中青蒿素的代谢模式，并评估大鼠自身诱导的程度。方法：c -14-青蒿素与人肝微粒体和口服青蒿素或安慰剂预处理的大鼠肝微粒体孵育。研究了c -14-青蒿素在经CYP2A6、CYP2B6和CYP3A4转化的人b淋巴母细胞样细胞株微粒体中的代谢命运。采用非线性混合效应建模方法对人肝微粒体数据和大鼠肝微粒体数据进行分析，并利用NONMEM进行初始池化。结果：在大鼠肝微粒体实验中检测到四种代谢物。最能描述数据的模型涉及三种初级代谢物，其中一种代谢物进一步代谢为次级代谢物。青蒿素预处理大鼠肝微粒体中四种代谢物的形成分别是其2.8倍、7.2倍、4.8倍和2.5倍。三种代谢物在人肝微粒体中形成；与在大鼠体内形成的三种代谢物具有相同的保留时间。最终模型由两个初级代谢物和一个次级代谢物组成，CYP2B6和CYP2A6分别影响主要代谢物和次要代谢物的形成速率。结论：CYP2B6和CYP2A6活性分别描述了人肝微粒体中主要和次要初级代谢物形成的变变性。经动脉素预处理后，大鼠肝微粒体中所有青蒿素代谢途径均被诱导。动物。我们建议将建模作为一种方法，从体外代谢率数据中区分和检测更复杂的代谢模式。版权所有：John Wiley Sons， Ltd。
Aims: The aims of the study were to characterise the metabolic pattern of artemisinin in human and rat liver microsomes and to assess the magnitude of auto-induction in the rat.Methods: C-14-artemisinin was incubated with human liver microsomes and with liver microsomes from rats pretreated with oral artemisinin or placebo. The metabolic fate of C-14-artemisinin in microsomes from human B-lymphoblastoid cell lines transformed with CYP2A6, CYP2B6 and CYP3A4 was also investigated. The human liver microsome data and the rat liver microsomes data were analysed by nonlinear mixed effects modelling and naive pooling using NONMEM, respectively.Results: Four metabolites were radiometrically detected in experiments with rat liver microsomes. The model that best described the data involved three primary metabolites of which one metabolite was further metabolised to a secondary metabolite. The formation of the four metabolites was induced 2.8, 7.2, 4.8 and 2.5-fold, respectively, in liver microsomes from rats pre-treated with artemisinin. Three metabolites were formed in human liver microsomes; having the same retention times as three of the metabolites formed in the rat. The final model consisted of two primary metabolites and a secondary metabolite with CYP2B6 and CYP2A6 influencing the formation rates of the major and minor primary metabolites, respectively.Conclusions: CYP2B6 and CYP2A6 activities described variability in the formation of the major and minor primary metabolites, respectively, in human liver microsomes. All artemisinin metabolic pathways in rat liver microsomes were induced in arternisinin pretreated. animals. We suggest modelling as a method for the discrimination and detection of more complex metabolic patterns from in vitro metabolism rate data. Copyright (C) 2003 John Wiley Sons, Ltd.