Moderate Correlations of in vitro versus in vivo Pharmacokinetics Questioning the Need of Early Microsomal Stability Testing

Eva Schrezenmeier, Frank S. Zollmann, Kerstin Seidel, Christian Boehm, Kristin Schmerbach, Melanie Kroh, Sebastian Kirsch, Sabrina Klare, Sarah Bernhard, Kai Kappert, Petra Goldin-Lang, Werner Skuballa, Thomas Unger, Heiko Funke-Kaiser*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Web of Science)

Abstract

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.
Original languageEnglish
Pages (from-to)307-315
JournalPharmacology
Volume90
Issue number5-6
DOIs
Publication statusPublished - 2012

Keywords

  • (Pro)renin receptor
  • Drug discovery
  • Correlation
  • Microsomal stability
  • In vivo pharmacokinetics
  • High-throughput screening

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