Moderate correlations of in vitro versus in vivo pharmacokinetics questioning the need of early microsomal stability testing.

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. Methods: 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. Results: 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. Conclusions: 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. Copyright (C) 2012 S. Karger AG, Basel