Recent development in high-throughput bioanalytical support for in vitro ADMET profiling

Abstract

Importance of the field: 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.

Areas covered in this review: 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.

What the reader will gain: 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.

Take home message: 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 potentiallya transform the existing bioanalytical paradigm in the future.

Keywords::

• ADMET profiling
• automated MS/MS condition optimization
• fast LC-MS/MS
• high-throughput bioanalysis
• integrated informatics
• leveraging technologies
• multiplexed LC-MS/MS
• online SPE-MS/MS

Acknowledgements

The authors thank all colleagues in Lead Profiling (LP) and Synthesis and Analysis Technology Team (SATT) of Bristol-Myers Squibb Co. for their support.

Notes

This box summarizes key points contained in the article.