Strategic Use of Plasma and Microsome Binding To Exploit in Vitro Clearance in Early Drug Discovery
Strategic Use of Plasma and Microsome Binding To Exploit in Vitro Clearance in Early Drug Discovery
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DOI：
10.1021/ml900012h
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发表时间：
2010-05-01
影响因子：
4.2
通讯作者：
Scott, Dennis O.
中科院分区：
文献类型：
--
作者：
Chang, George;Steyn, Stefanus J.;Scott, Dennis O.
表观内在清除率（CLia）由微粒体稳定性测定是药物发现的基石。分类箱通常应用于这个终点，以方便分析。然而，这样的箱子忽略了几个ADME参数上表观固有微粒体间隙的相互依赖性质。将CLia作为代谢稳定性和潜在剂量的决定因素更为合适。在这种情况下，适当考虑与微粒体和血浆的非特异性结合，考虑具有较高CLia的化合物可能是有必要的。潜在的好处是，在项目的早期阶段，有可能增加hit的数量或化学多样性的评估。
Apparent intrinsic clearance (CLia) determined from microsomal stability assays is a cornerstone in drug discovery. Categorical bins are routinely applied to this end point to facilitate analysis. However, such bins ignore the interdependent nature of apparent intrinsic microsome clearance on several ADME parameters. Considering CLia as a determinant for both metabolic stability and potential dose is more appropriate. In this context with proper accounting for nonspecific binding to microsomes and plasma, consideration of compounds with higher CLia may be warranted. The underlying benefit is the potential increase in the number of hits or chemical diversity for evaluation during the early stages of programs.