title: Moderate correlations of in vitro versus in vivo pharmacokinetics questioning the need of early microsomal stability testing.
abstract: OBJECTIVE
  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.
authors.affiliation: Center for Cardiovascular Research/Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Schrezenmeier
authors.forename: Frank S
authors.initials: FS
authors.lastname: Zollmann
authors.forename: Kerstin
authors.initials: K
authors.lastname: Seidel
authors.forename: Christian
authors.initials: C
authors.lastname: Böhm
authors.forename: Kristin
authors.initials: K
authors.lastname: Schmerbach
authors.forename: Melanie
authors.initials: M
authors.lastname: Kroh
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kirsch
authors.forename: Sabrina
authors.initials: S
authors.lastname: Klare
authors.forename: Sarah
authors.initials: S
authors.lastname: Bernhard
authors.forename: Kai
authors.initials: K
authors.lastname: Kappert
authors.forename: Petra
authors.initials: P
authors.lastname: Goldin-Lang
authors.forename: Werner
authors.initials: W
authors.lastname: Skuballa
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.forename: Heiko
authors.initials: H
authors.lastname: Funke-Kaiser
mesh_terms: D000826:Animal Testing Alternatives / Q000379:methods; D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006207:Half-Life; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results
chemical_list: D004364:Pharmaceutical Preparations