Analytical Chemistry, Platform Technology and Science, GlaxoSmithKline, Stevenage, UK.
J Pharm Sci. 2012 Nov;101(11):4155-69. doi: 10.1002/jps.23305. Epub 2012 Aug 28.
The concepts of drug efficiency (D(eff) ) and Drug Efficiency Index (DEI) have been recently introduced as useful parameters to optimize the absorption, distribution, metabolism, elimination/excretion, and toxicity properties and in vivo efficacy potential of molecules during lead optimization and at pre-clinical stages. The available free drug concentration relative to dose depends on the compound's bioavailability, clearance, and the nonspecific binding to proteins and phospholipids. In this paper, we have demonstrated, using the data of over 115 known drug molecules, that the nonspecific binding can be determined in vitro very efficiently using biomimetic high-performance liquid chromatography measurements. DEI can therefore be estimated from in vitro measurements. The data show that high in vitro DEI values can be associated with lower efficacious dose. A strategy is described of how to use the DEI parameter during early lead optimization. An example is given to highlight the advantages of optimizing on DEI value rather than on potency alone. In order to facilitate the in silico compound design, correlation between in vitro DEI and in silico ligand efficiency parameters such as ligand lipophilicity efficiency has been revealed, suggesting the potential use of these efficiency-related parameters across lead optimization.
药物效率（D(eff)）和药物效率指数（DEI）的概念最近被引入，作为优化分子在先导优化和临床前阶段的吸收、分布、代谢、消除/排泄和毒性特性以及体内疗效潜力的有用参数。相对于剂量的可用游离药物浓度取决于化合物的生物利用度、清除率和与蛋白质和磷脂的非特异性结合。在本文中，我们使用超过 115 种已知药物分子的数据证明，使用仿生高效液相色谱测量可以非常有效地在体外确定非特异性结合。因此，可以从体外测量估计 DEI。数据表明，高体外 DEI 值可与较低的有效剂量相关。描述了一种在早期先导优化期间如何使用 DEI 参数的策略。提供了一个示例来说明优化 DEI 值而不是单独优化效力的优势。为了便于计算机化合物设计，揭示了体外 DEI 与体外配体效率参数（如配体脂溶性效率）之间的相关性，表明这些效率相关参数在先导优化过程中具有潜在的用途。
