Davis A M, Webborn P J, Salt D W
Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood, Leicestershire, United Kingdom.
Drug Metab Dispos. 2000 Feb;28(2):103-6.
The optimization of pharmacokinetic properties remains one of the most challenging aspects of drug design. Key parameters, clearance and volume of distribution, are multifactorial, which makes deriving structure-pharmacokinetic relationships difficult. The correction of clearance and volume of distribution for the unbound fraction in plasma is one approach taken that has enabled quantitative structure-pharmacokinetic relationships to be derived. Three published data-sets where unbound parameters have been correlated with lipophilicity have been reanalyzed. The reanalysis has shown that high correlation coefficients can be achieved without any true correlation in the data and can lead to misinterpretation of the ways in which lipophilicity influences pharmacokinetics. Randomization procedures are proposed as a more robust method of assessing significance.
药代动力学性质的优化仍然是药物设计中最具挑战性的方面之一。关键参数，清除率和分布容积，是多因素的，这使得推导结构-药代动力学关系变得困难。校正血浆中游离分数的清除率和分布容积是一种已采用的方法，它使得能够推导出定量结构-药代动力学关系。对已发表的三个游离参数与亲脂性相关的数据集进行了重新分析。重新分析表明，在数据中没有任何真实相关性的情况下也能获得高相关系数，这可能导致对亲脂性影响药代动力学方式的错误解读。建议采用随机化程序作为评估显著性的更可靠方法。
