Assessment of Biliary Clearance in Early Drug Discovery using Sandwich-cultured Hepatocyte Model

It is challenging to predict biliary clearance (CLb) for new chemical entities (NCEs) in early drug discovery. Although sandwich-cultured hepatocyte (SCH) model has offered a valuable tool for characterizing hepatobiliary disposition and drug-drug interaction potential of NCEs, no comprehensive study was reported to project in vivo biliary clearance (in vivo CLb,observed) potential using in vitro SCH model during the drug discovery stage. In this study, the CLb of 110 discovery compounds was evaluated using rat SCH model. Parallel artificial membrane permeability assay, Caco-2, and rat liver microsomes were employed in parallel to explore the interplay of biliary excretion with cellular permeability and liver metabolism. Selected compounds were further tested in bile-duct-cannulated rats, confirming the value of the SCH model for ranking and predicting in vivo CLb,observed during drug discovery. For compounds with extremely low passive permeability and metabolism, rat SCH may underestimate in vivo CLb,observed. The combination of passive permeability, metabolic intrinsic clearance, and the SCH model could serve as an initial screening platform for biliary excretion potential as well as a means for improving compound liabilities and properties. A preliminary evaluation strategy was proposed to highlight biliary excretion risk evaluation during the drug discovery process. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:1898-1908, 2012