title: Practical permeability-based hepatic clearance classification system (HepCCS) in drug discovery.
abstract: BACKGROUND
  The use of liver microsomes and hepatocytes to predict total in vivo clearance is standard practice in the pharmaceutical industry; however, metabolic stability data alone cannot always predict in vivo clearance accurately.
  
  
  RESULTS
  Apparent permeability generated from Mardin-Darby canine kidney cells and rat hepatocyte uptake for 33 discovery compounds were obtained.
  
  
  CONCLUSIONS
  When there is underprediction of in vivo clearance, compounds with low apparent permeability (less than 3 × 10(-6) cm/s) all exhibited hepatic uptake. A systematic approach in the form of a classification system (hepatic clearance classification system) and decision tree that will help drug discovery scientists understand in vitro-in vivo clearance prediction disconnect early is proposed.
authors.affiliation: Department of Drug Metabolism & Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Fan
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.forename: Leonid M
authors.initials: LM
authors.lastname: Berezhkovskiy
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cheong
authors.forename: Emile G
authors.initials: EG
authors.lastname: Plise
authors.forename: S Cyrus
authors.initials: SC
authors.lastname: Khojasteh
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D027701:Organic Cation Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D053719:Tandem Mass Spectrometry
chemical_list: D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D004364:Pharmaceutical Preparations; C491012:Slc22a2 protein, mouse