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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Shou
Wilson Z
WZ
Applied Biotechnology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA. wilson.shou@bms.com
Zhang
Jun
J
D002853:Chromatography, Liquid / Q000295:instrumentation / Q000379:methods* / Q000639:trends; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods* / Q000639:trends; D006801:Humans; D013058:Mass Spectrometry / Q000295:instrumentation / Q000379:methods* / Q000639:trends; D012984:Software