title: Development of a high-throughput in vitro assay using a novel Caco-2/rat hepatocyte system for the prediction of oral plasma area under the concentration versus time curve (AUC) in rats.
abstract: BACKGROUND
  Previously, we have shown that a novel Caco-2/human hepatocyte system is a useful model for the prediction of oral bioavailability in humans. In this study, we attempted to use a similar system in a high-throughput screening mode for the selection of new compound entities (NCE) in drug discovery.
  
  
  METHODS
  A total of 72 compounds randomly selected from three different chemotypes were dosed orally in rats. In vivo plasma area under the concentration versus time curve (AUC) from 0-6 h of the parent compound was determined. The same compounds were also tested in the Caco-2/rat hepatocyte system. In vitro AUC from 0-3 h in the Caco-2 rat hepatocyte system was determined.
  
  
  RESULTS
  The predictive usefulness of the Caco-2/rat hepatocyte system was evaluated by comparing the in vivo plasma AUC and the in vitro AUC. Linear regression analysis showed a reasonable correlation (R2 = 0.5) between the in vivo AUC and the in vitro AUC. Using 0.4 microM h in vivo AUC as a cut-off, compounds were categorized as either low or high AUC. The in vitro AUC successfully matched the corresponding in vivo category for sixty-three out of seventy-two compounds.
  
  
  CONCLUSIONS
  The results presented in this study suggest that the Caco-2/rat hepatocyte system may be used as a high-throughput screen in drug discovery for pharmacokinetic behaviors of compounds in rats.
authors.affiliation: Schering-Plough Research Institute, K-15-2-2700, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. kuo-chi.cheng@spcorp.com
authors.forename: K-C
authors.initials: KC
authors.lastname: Cheng
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Hsieh
authors.forename: Diana
authors.initials: D
authors.lastname: Montgomery
authors.forename: Tongtong
authors.initials: T
authors.lastname: Liu
authors.forename: Ronald E
authors.initials: RE
authors.lastname: White
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001681:Biological Assay; D018938:Caco-2 Cells; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D016014:Linear Models; D011237:Predictive Value of Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D015262:Xenobiotics / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D015262:Xenobiotics