Center for Cardiovascular Research/Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Pharmacology. 2012;90(5-6):307-15. doi: 10.1159/000343241. Epub 2012 Oct 4.
BACKGROUND/AIMS: Putative in vitro-in vivo correlations of pharmacokinetic (PK) parameters are regarded as a prerequisite to filter hits derived from high-throughput screening (HTS) approaches for subsequent murine in vivo PK studies.
In this study, we assessed stabilities in rat and human microsomes of 121 compounds from an early, academic drug discovery programme targeting the (pro)renin receptor and correlated the respective data with single-dose, in vivo PK parameters of 22 hits administered intravenously in rats.
After transformation of in vitro half-lives to predicted in vivo hepatic clearances, r(2) regarding in vitro-in vivo clearance correlations were 0.31 and 0.27 for the rat and human species, respectively.
Our data concerning structurally diverse real-world compounds indicate that microsomal stability testing is not a tool to triage early compounds for in vivo PK testing.
背景/目的：将药代动力学 (PK) 参数的体外-体内相关性假设作为从高通量筛选 (HTS) 方法中筛选后续用于啮齿动物体内 PK 研究的命中化合物的前提条件。
在这项研究中，我们评估了 121 种来自早期学术药物发现项目的化合物在大鼠和人微粒体中的稳定性，这些化合物的靶点是 (pro) 肾素受体，并将各自的数据与 22 种在大鼠体内静脉给药的命中化合物的单剂量体内 PK 参数进行了相关性分析。
将体外半衰期转化为预测的体内肝清除率后，大鼠和人体物种的体外-体内清除率相关性的 r(2) 值分别为 0.31 和 0.27。
我们关于结构多样的真实世界化合物的数据表明，微粒体稳定性测试不是用于筛选早期化合物进行体内 PK 测试的工具。
