title: In vitro-in vivo correlation for low-clearance compounds using hepatocyte relay method.
abstract: In vitro-in vivo correlation (IVIVC) of intrinsic clearance in preclinical species of rat and dog was established using the hepatocyte relay method to support high-confidence prediction of human pharmacokinetics for low-clearance compounds. Good IVIVC of intrinsic clearance was observed for most of the compounds, with predicted values within 2-fold of the observed values. The exceptions involved transporter-mediated uptake clearance or metabolizing enzymes with extensive extrahepatic contribution. This is the first assay available to address low clearance challenges in preclinical species for IVIVC in drug discovery. It extends the utility of the hepatocyte relay method in addressing low clearance issues.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut.
authors.forename: Li
authors.initials: L
authors.lastname: Di
authors.forename: Karen
authors.initials: K
authors.lastname: Atkinson
authors.forename: Christine C
authors.initials: CC
authors.lastname: Orozco
authors.forename: Carrie
authors.initials: C
authors.lastname: Funk
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Thomas S
authors.initials: TS
authors.lastname: McDonald
authors.forename: Beijing
authors.initials: B
authors.lastname: Tan
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.forename: Cheng
authors.initials: C
authors.lastname: Chang
authors.forename: R Scott
authors.initials: RS
authors.lastname: Obach
mesh_terms: D000818:Animals; D004285:Dogs; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical; D022781:Hepatocytes / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D008657:Metabolic Clearance Rate / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D026901:Membrane Transport Proteins