title: Prediction of total hepatic clearance by combining metabolism, transport, and permeability data in the in vitro-in vivo extrapolation methods: emphasis on an apparent fraction unbound in liver for drugs.
abstract: Poulin and coworkers recently proposed in three manuscripts (2012. J Pharm Sci 101:838-851; 2012. J Pharm Sci 101:4308-4326; and 2013. J Pharm Sci 102:in press) a novel in vitro-to-in vivo extrapolation (IVIVE) method for clearance (CL) involving estimation of apparent fraction unbound in liver (fu(liver)) based on albumin-facilitated hepatic uptake and correction of unbound drug according to the ionization fraction either side of the plasma membrane. This novel IVIVE method has improved the prediction accuracy, and, hence, reduced the bias in predicting hepatic metabolic CL referring to plasma kinetics of several acidic/neutral drugs in preclinical species and humans either based on microsomal or hepatocyte data. So far, the prediction performance of this novel IVIVE method has been assessed for metabolic CL only. Because CL might also be governed by transporters effect and/or permeation limitation in addition to metabolism, an extension of the proposed IVIVE method from metabolic data to transport and permeability data was necessary. Therefore, it was assumed that the concept should also work for multiple CL processes predictions because it is applicable as long as the drug gets to the hepatocyte cell surface. In this study, the proposed IVIVE method was assessed using a large database of predictions of total hepatic CL in rats and humans by combining in vitro hepatocyte data on metabolism, transport, and permeability. The proposed IVIVE method is similarly effective in minimizing average prediction bias and improves accuracy unlike other IVIVE methods. Overall, the present study confirms the utility of the novel IVIVE method for predicting total hepatic CL of drugs under in vivo conditions either by considering metabolism data only or combining metabolism with transporter and permeability data. This study will facilitate the predictions of total hepatic CL in physiologically based pharmacokinetics (PBPK) model.
authors.affiliation: patrick-poulin@videotron.ca
authors.forename: Patrick
authors.initials: P
authors.lastname: Poulin
mesh_terms: D000465:Algorithms; D000818:Animals; D001692:Biological Transport; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000097:blood* / Q000378:metabolism*; D010599:Pharmacokinetics; D051381:Rats
chemical_list: D004364:Pharmaceutical Preparations