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Assessment of biliary clearance in early drug discovery using sandwich-cultured hepatocytes model (SCH)

Pan, Guoyu, Boiselle, Carri and Wang, Jianling (2012) Assessment of biliary clearance in early drug discovery using sandwich-cultured hepatocytes model (SCH). Journal of Pharmaceutical Sciences. ISSN 0022-3549


It is challenging to predict biliary clearance for new chemical entities (NCEs) in the early stages of drug discovery. Sandwich-cultured hepatocytes (SCH) have been reported to be a valuable tool for characterizing the hepatobiliary disposition and drug-drug interaction (DDI) potential of drug candidates; however, there is no comprehensive report projecting in vivo biliary clearance potential using in vitro SCH model during the drug discovery stage. The objective of this study was to determine if SCH can be used as an in vitro flagging tool and to identify potential connections between various in vitro ADME profiling assays. In this study, the biliary clearance of 110 discovery compounds was evaluated using the rat SCH model. PAMPA, Caco-2, and rat liver microsomes were employed in parallel to explore the relationships among the in vitro biliary excretion, cellular permeability, and liver metabolism of test compounds. Selected compounds were further tested in bile duct cannulated rats for IVIVC purpose. It was found that the rat SCH model proved to be a valuable tool for ranking and predicting in vivo biliary clearance during drug discovery. Passive permeability and metabolism may influence test compound biliary excretion. For compounds with extremely low passive permeability and metabolism, rat SCH may underestimate in vivo biliary clearance. The combination of passive permeability, metabolic intrinsic clearance, and the SCH model could serve as an initial screening platform for bile 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.

Item Type: Article
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Additional Information: archiving not allowed on institutional repository
Keywords: Sandwich-cultured hepatocytes, passive permeability, transporter, metabolism
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15


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