Lai Yurong
Pfizer Global Research & Development, Pfizer, Inc., Department of Pharmacokinetic, Dynamics, & Metabolism, St Louis Laboratory, 700 Chesterfield Parkway West, St Louis Chesterfield, MO 63017, USA.
Expert Opin Drug Metab Toxicol. 2009 Oct;5(10):1175-87. doi: 10.1517/17425250903127234.
Increasing challenges include the application of in vitro/in vivo models for prediction of safety and pharmacokinetic profiles for the compounds entering drug development that are mainly secreted from bile. Species differences in biliary excretion have long been recognized and complicate the extrapolation of human pharmacokinetics from preclinical species or in vitro models. The currently available literature has been reviewed with a focus on drug-drug interactions mediated by hepatic drug transporters and the available tools for transporter assessments. Therefore, our incomplete understanding of interspecies differences and in vitro liver models poses a serious challenge in predicting human pharmacokinetics and/or safety profiles when the compounds are predominantly secreted from bile. This review outlines species differences in hepatobiliary secretion and the recent effort in understanding the absolute difference in hepatobiliary transporter expressions across species. In addition, understanding the expression of hepatobiliary transporters between in vitro hepatocyte models and in vivo to improve the prediction of biliary secretion is also discussed.
越来越多的挑战包括应用体外/体内模型来预测进入药物研发阶段且主要通过胆汁分泌的化合物的安全性和药代动力学特征。胆汁排泄的种属差异早已被认识到，这使得从临床前物种或体外模型推断人体药代动力学变得复杂。本文回顾了现有文献，重点关注肝脏药物转运体介导的药物相互作用以及用于转运体评估的现有工具。因此，当化合物主要通过胆汁分泌时，我们对种属差异和体外肝脏模型的不完全理解，给预测人体药代动力学和/或安全性特征带来了严峻挑战。本综述概述了肝胆分泌的种属差异以及近期在了解跨物种肝胆转运体表达绝对差异方面所做的努力。此外，还讨论了了解体外肝细胞模型与体内肝胆转运体的表达，以改善胆汁分泌预测的相关内容。
