Wang Jianling
ADME Profiling Cambridge, Metabolism and Pharmacokinetics, Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
Curr Pharm Des. 2009;15(19):2195-219. doi: 10.2174/138161209788682514.
The high attrition rate in drug development and the deteriorated drug ability as a result of the shifted chemical space of new therapeutic target for unmet medical needs have posed drastic challenges in current drug discovery. It has triggered the strategic transition in the past decade into parallel assessment of efficacy and comprehensive ADMET (absorption, distribution, metabolism, elimination and toxicity) properties of new chemical entities (NCEs) in the lead selection and optimization stages, to convert chemically a problematic NCE to an "all-around" candidate. This review summarizes multiple in silico, in vitro and in vivo ADMET filters developed and implemented in various stages of drug discovery to flag potential ADMET issues in the clinic. The full awareness of the benefits and limitations of each tool assures right questions to be answered using right tools at right time. The integrated ADMET risk assessment will allow project teams to have a clear vision in terms of the competitive position of own NCEs against comparable marketed drugs.
药物研发中的高淘汰率以及由于新治疗靶点化学空间的转变导致的药物能力下降，以满足未满足的医疗需求，给当前的药物发现带来了巨大挑战。这在过去十年中引发了战略转变，即在先导化合物选择和优化阶段对新化学实体（NCEs）的疗效和综合ADMET（吸收、分布、代谢、排泄和毒性）特性进行并行评估，以便将有问题的NCE化学转化为“全面”的候选药物。本综述总结了在药物发现的各个阶段开发和实施的多种计算机模拟、体外和体内ADMET筛选方法，以标记临床中潜在的ADMET问题。充分了解每种工具的优缺点可确保在正确的时间使用正确的工具回答正确的问题。综合ADMET风险评估将使项目团队能够清楚地了解自己的NCE相对于同类上市药物的竞争地位。
