Di Li, Obach R Scott
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut, 06340, USA,
AAPS J. 2015 Mar;17(2):352-7. doi: 10.1208/s12248-014-9691-7. Epub 2015 Jan 8.
As a result of high-throughput ADME screening, early metabolite identification, and exploration of novel chemical entities, low-intrinsic-clearance compounds continue to increase in drug discovery portfolios. Currently available in vitro tools have limited resolution below a certain intrinsic clearance value, which can lead to overestimation of clearance and dose and underestimation of half-life. Significant advances have been made in recent years and novel approaches have been developed to address the challenges of low clearance in drug discovery, such as the hepatocyte relay method, use of qNMR-based standards of biosynthesized drug metabolites to permit monitoring metabolite formation, coculture hepatocyte systems, and the time depending modeling approach. Future development in the field will enable faster, more precise, and lower cost profiling of the properties of low-clearance compounds for intrinsic clearance, metabolite identification, and reaction phenotyping.
由于高通量药物代谢及药物动力学（ADME）筛选、早期代谢物鉴定以及新型化学实体的探索，低内在清除率化合物在药物研发组合中持续增加。目前可用的体外工具在低于一定内在清除率值时分辨率有限，这可能导致清除率和剂量的高估以及半衰期的低估。近年来已取得显著进展，并开发了新方法来应对药物研发中低清除率的挑战，如肝细胞接力法、使用基于定量核磁共振（qNMR）的生物合成药物代谢物标准来监测代谢物形成、共培养肝细胞系统以及时间依赖性建模方法。该领域的未来发展将能够更快、更精确且成本更低地对低清除率化合物的内在清除率、代谢物鉴定和反应表型特征进行分析。
