A TIME HIERARCHY-BASED MODEL FOR KINETICS OF DRUG DISPOSITION AND ITS USE IN QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS
A TIME HIERARCHY-BASED MODEL FOR KINETICS OF DRUG DISPOSITION AND ITS USE IN QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS
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DOI：
10.1002/jps.2600810902
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发表时间：
1992-09-01
影响因子：
3.8
通讯作者：
SEYDEL, JK
中科院分区：
文献类型：
--
作者：
BALAZ, S;WIESE, M;SEYDEL, JK
通过使用决定药物在生物系统中命运的过程的时间层次（吸收、运输、分布、蛋白质结合和消除），在亚细胞水平上为药代动力学的处置阶段制定了一个单室开放模型。所得到的处置函数描述了药物在细胞内处置的动力学，由它们的疏水性、酸性或碱性、对蛋白质的亲和力和消除速率参数决定。结构-活性关系，基于结合了超热力学关系的函数，很好地符合文献数据（固定时间生物活性-疏水性谱，有机化合物的微生物降解动力学，芬太尼衍生物在大鼠体内的镇痛作用动力学）。该方法的应用，为基于模型的定量结构-时间-活动关系的构建奠定了基础，讨论了不同复杂性的生物系统。
By using the time hierarchy of the processes determining the fate of drugs in biosystems (absorption, transport, distribution, protein binding, and elimination), a one-compartment open model is formulated at a subcellular level for the disposition phase of pharmacokinetics. The resulting disposition function describes the kinetics of the intracellular disposition of drugs as determined by their hydrophobicity, acidity or basicity, affinity to proteins, and rate parameters of elimination. Structure-activity relationships, based on the function with incorporated extrathermodynamic relations, fit the literature data well (fixed-time bioactivity-hydrophobicity profiles, kinetics of microbial degradation of organic compounds, and kinetics of analgesic effects of fentanyl derivatives in rats). Application of the approach, creating a basis for the construction of model-based quantitative structure-time-activity relationships, to biosystems of varying complexity is discussed.