Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Brussels, Belgium.
Drug Metab Rev. 2013 May;45(2):196-217. doi: 10.3109/03602532.2012.756010. Epub 2013 Feb 1.
Before any drug can be placed on the market, drug efficacy and safety must be ensured through rigorous testing. Animal models are used for this purpose, though currently increasing attention goes to the use of alternative in vitro systems. In particular, liver-based testing platforms that allow the prediction of pharmacokinetic (PK) and pharmacotoxicological properties during the early phase of drug development are of interest. They also enable the screening of potential effects on hepatic drug transporters. The latter are known to affect drug metabolism and disposition, thereby possibly underlying drug-drug interactions, which, in turn, may result in liver toxicity. Clearly, stable in vivo-like functional expression of drug transporters in hepatic in vitro settings is a prerequisite to be applicable in routine PK and pharmacotoxicological testing. In the first part of the article, an updated overview of hepatic drug transporters is provided, followed by a state-of-the-art review of drug-transporter production and activity in primary hepatocyte cultures (PHCs), being the gold-standard in vitro system. Specific focus is hereby put on strategies to maintain long-term functional expression, in casu of drug transporters, in these systems. In the second part, the use of PHCs to assess hepatobiliary transport and transporter-mediated interactions is outlined.
在任何药物投放市场之前，都必须通过严格的测试来确保其疗效和安全性。为此目的使用了动物模型，尽管目前越来越关注替代体外系统的使用。特别是，基于肝脏的测试平台允许在药物开发的早期阶段预测药代动力学（PK）和药理毒性特性。它们还能够筛选对肝药物转运体的潜在影响。已知后者会影响药物代谢和处置，从而可能导致药物相互作用，这反过来又可能导致肝毒性。显然，在肝体外环境中稳定的类似于体内的药物转运体的功能表达是在常规 PK 和药理毒性测试中应用的前提。本文的第一部分提供了对肝药物转运体的最新概述，随后对原代肝细胞培养物（PHC）中的药物-转运体生产和活性的最新技术进行了综述，这是体外的金标准系统。在此特别关注在这些系统中维持药物转运体的长期功能表达的策略。在第二部分中，概述了使用 PHC 评估肝胆转运和转运体介导的相互作用。
