title: Comparison of the use of liver models for predicting drug clearance using in vitro kinetic data from hepatic microsomes and isolated hepatocytes.
abstract: OBJECTIVE
  To compare three liver models (well-stirred, parallel tube, and dispersion) for the prediction of in vivo intrinsic clearance (CL(int)), hepatic clearance (CLh). and hepatic availability (Fh) of a wide range of drugs in the rat using in vitro data from two in vitro sources.
  
  
  METHODS
  In vitro CL(int) was obtained from studies using isolated rat hepatocytes (35 drugs) or rat liver microsomes (52 drugs) and used to predict in vivo CL(int) using reported scaling factors, and subsequently CLh and Fh were predicted based on the three liver models. In addition, in vivo CL(int) values were calculated from the reported values of CLh based on each of the three models.
  
  
  RESULTS
  For all of the parameters, predictions from hepatocyte data were consistently more accurate than those from microsomal data. Comparison of in vitro and in vivo CL(int) values demonstrated that the dispersion model and the parallel tube model were comparable and more accurate (less bias, more precise) than the well-stirred model. For CLh and Fh prediction, the three models performed similarly.
  
  
  CONCLUSIONS
  Considering the statistics of the predictions for three liver models, the use of parallel tube model is recommended for the evaluation of in vitro CL(int) values both from microsomes and hepatocytes. However, for the prediction of the in vivo drug (hepatic) clearance from in vitro data, as there are minimal differences between the models, the use of the well-stirred liver model is recommended.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Ito
authors.forename: J Brian
authors.initials: JB
authors.lastname: Houston
mesh_terms: D000465:Algorithms; D000818:Animals; D001682:Biological Availability; D002469:Cell Separation; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D011237:Predictive Value of Tests; D051381:Rats
chemical_list: D004364:Pharmaceutical Preparations