title: Investigation of the utility of published in vitro intrinsic clearance data for prediction of in vivo clearance.
abstract: BACKGROUND
  This study was conducted to compare and contrast published in vitro intrinsic clearance values reported for compounds from different laboratories and the predictivity of these data to project in vivo clearance.
  
  
  METHODS
  A total of 103 compounds were selected for investigation and an exhaustive literature search was conducted to identify in vitro intrinsic clearance (CL,i) values for comparative purposes. The simple well-stirred model was used to predict in vivo clearance using these in vitro intrinsic clearance values.
  
  
  RESULTS
  Data were available in the literature for <10% of the compounds of interest in rat, dog, monkey, or human S9, as well as <10% for dog or monkey microsomes or hepatocytes. Therefore, this comparative exercise was limited to rat and human microsomes and hepatocytes. Examination of the available CL,i values indicated a substantial (up to 100 s-fold) variation in values reported in the literature; this variability translated into substantial variation in predicted in vivo clearance.
  
  
  CONCLUSIONS
  The literature paucity and variability described here demonstrate the importance of generating experimentally consistent de novo CL,i data for the purpose of method validation or in vitro-in vivo scaling.
authors.affiliation: Preclinical Drug Discovery, Cardiovascular and Urogenital Center of Excellence in Drug Discovery, GlaxoSmithKline, UW 2725, 709 Swedeland Road, King of Prussia, PA 19406, USA. Rakesh.2.Nagilla@gsk.com
authors.forename: Rakesh
authors.initials: R
authors.lastname: Nagilla
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Frank
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Jolivette
authors.forename: Keith W
authors.initials: KW
authors.lastname: Ward
mesh_terms: D000818:Animals; D016208:Databases, Factual; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D000882:Haplorhini; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D004364:Pharmaceutical Preparations; D011237:Predictive Value of Tests; D051381:Rats; D000091243:Ribosomal Protein S9; D012269:Ribosomal Proteins / Q000378:metabolism; D015262:Xenobiotics / Q000493:pharmacokinetics*
chemical_list: D004364:Pharmaceutical Preparations; D000091243:Ribosomal Protein S9; D012269:Ribosomal Proteins; D015262:Xenobiotics