Practical permeability-based hepatic clearance classification system (HepCCS) in drug discovery. (December 2014)

• Record Type: Journal Article
• Authors: Fan, Peter W; Song, Yang; Berezhkovskiy, Leonid M; Cheong, Jonathan; Plise, Emile G; Khojasteh, S Cyrus
• Is Part Of: Future medicinal chemistry. Volume 6:Number 18(2014)
• Page Start: 1995
• Page End: 2012
• Publication Date: 2014-12
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.4155/fmc.14.141
• Languages: English
• ISSNs: 1756-8919

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.Conclusion: 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.