Applied Biotechnology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA.
Expert Opin Drug Metab Toxicol. 2010 Mar;6(3):321-36. doi: 10.1517/17425250903547829.
High-throughput in vitro ADMET (absorption, distribution, metabolism, excretion and toxicity) profiling has become an important common practice in the pharmaceutical industry to assess compound liability early in the drug discovery process. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the bioanalytical method of choice for ADMET profiling assays that require compound-specific detection. However, the in vitro ADMET profiling environment, with its unique bioanalytical requirements of analyzing many samples generated from many discrete compounds in a high-throughput fashion, poses significant challenges for the traditional LC-MS/MS technology and process workflow, which were originally designed and optimized for single-compound bioanalysis.
This article reviews advances made during the last several years in both conventional high-throughput LC-MS/MS approaches and a number of promising novel MS-based technologies specifically developed to address the unique challenges in an ADMET environment. The advantages and limitations of each technology are also discussed. In addition, software solutions to enable and integrate these hardware improvements into the high-throughput ADMET workflow are reviewed.
The reader will gain an updated knowledge of the state-of-the-art technologies and practices, as well as promising novel MS-based methodologies in the field of ADMET bioanalysis.
Recent advances such as automated MS/MS optimization, high-speed and multiplexed LC separation, and integrated software support have significantly increased the speed and quality of ADMET bioanalysis using LC-MS/MS. Emerging novel technologies in front-end sample introduction, ionization and mass analysis are expected to further push the current throughput limit and potentially transform the existing bioanalytical paradigm in the future.
高通量体外 ADMET（吸收、分布、代谢、排泄和毒性）分析已成为药物发现过程早期评估化合物不良倾向的制药行业的重要常规做法。液相色谱-串联质谱（LC-MS/MS）是需要化合物特异性检测的 ADMET 分析测定的首选生物分析方法。然而，体外 ADMET 分析环境具有独特的生物分析要求，需要以高通量方式分析来自许多离散化合物的许多样品，这对最初设计和优化用于单化合物生物分析的传统 LC-MS/MS 技术和工艺工作流程构成了重大挑战。
本文综述了过去几年中在常规高通量 LC-MS/MS 方法以及许多专门开发以解决 ADMET 环境中独特挑战的有前途的新型基于 MS 的技术方面取得的进展。还讨论了每种技术的优缺点。此外，还回顾了能够将这些硬件改进集成到高通量 ADMET 工作流程中的软件解决方案。
读者将获得 ADMET 生物分析领域最新技术和实践以及有前途的新型基于 MS 的方法的最新知识。
自动化 MS/MS 优化、高速和多路复用 LC 分离以及集成软件支持等最新进展显著提高了使用 LC-MS/MS 进行 ADMET 生物分析的速度和质量。前端样品引入、离子化和质量分析方面新兴的新型技术有望进一步推动当前的高通量限制，并有可能在未来改变现有的生物分析范例。
