Assessment of Biliary Clearance in Early Drug Discovery Using Sandwich-Cultured Hepatocyte Model
Assessment of Biliary Clearance in Early Drug Discovery Using Sandwich-Cultured Hepatocyte Model
复制标题
使用三明治培养肝细胞模型评估早期药物发现中的胆道清除率
DOI：
10.1002/jps.23070
复制
发表时间：
2012-05-01
影响因子：
3.8
通讯作者：
Wang, Jianling
中科院分区：
文献类型：
--
作者：
Pan, Guoyu;Boiselle, Carri;Wang, Jianling
新化学实体（NCEs）的胆道清除率（CLb）预测在药物早期发现中具有挑战性。虽然三明治培养肝细胞（SCH）模型为表征NCEs的肝胆处置和药物-药物相互作用潜力提供了有价值的工具，但在药物发现阶段，尚未有综合研究报道使用体外SCH模型预测体内胆道清除（体内CLb，（观察到））的潜力。本研究采用大鼠SCH模型对110种新发现化合物的CLb进行了评价。采用平行人工膜通透性实验、Caco-2和肝微粒体，探讨胆排泄与细胞通透性和肝脏代谢的相互作用。选定的化合物在胆管插管的大鼠中进一步测试，证实了SCH模型在药物发现过程中对体内CLb的排序和预测（观察到的）价值。对于被动渗透率和代谢极低的化合物，大鼠SCH可能低估体内CLb（观察到）。结合被动通透性、代谢固有清除率和SCH模型，可作为胆道排泄潜能的初步筛选平台，以及改善化合物性能的手段。提出了一种初步的评价策略，以突出药物发现过程中的胆道排泄风险评价。(C) 2012中国医药科学与技术杂志[J] .中国医药科学[J] . 32 (1): 398 - 398, 2012
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. (C) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101: 1898-1908, 2012