A high throughput metabolic stability screening workflow with automated assessment of data quality in pharmaceutical industry

Journal of Chromatography. a
Rongda XuDaniel B Kassel

Abstract

One of the most commonly performed in vitro ADME assays during the lead generation and lead optimization stage of drug discovery is metabolic stability evaluation. Metabolic stability is typically assessed in liver microsomes, which contain Phase I metabolizing enzymes, mainly cytochrome P450 enzymes (CYPs). The amount of parent drug metabolized by these CYPs is determined by LC/MS/MS. The metabolic stability data are typically used to rank order compounds for in vivo evaluation. We describe a streamlined and intelligent workflow for the metabolic stability assay that permits high throughput analyses to be carried out while maintaining the standard of high quality. This is accomplished in the following ways: a novel post-incubation pooling strategy based on cLogD(3.0) values, coupled with ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS), enables sample analysis times to be reduced significantly while ensuring adequate chromatographic separation of compounds within a group, so as to reduce the likelihood of compound interference. Assay quality and fast turnaround of data reports is ensured by performing automated real-time intelligent re-analysis of discrete samples for compounds that do not pass use...Continue Reading

References

Feb 14, 2002·Journal of the American Society for Mass Spectrometry·Rongda XuCharles Z C Liu
Jan 6, 2004·Journal of Pharmaceutical Sciences·John H Ansede, Dhiren R Thakker
Mar 17, 2004·Journal of Pharmaceutical and Biomedical Analysis·Kelly M JenkinsRobyn A Rourick
Jun 9, 2004·Current Opinion in Chemical Biology·Daniel B Kassel
Aug 3, 2004·Nature Reviews. Drug Discovery·Ismail Kola, John Landis
Dec 1, 2004·Rapid Communications in Mass Spectrometry : RCM·Enaksha R WickremsinheAjai K Chaudhary
Sep 27, 2005·Current Topics in Medicinal Chemistry·Suresh K BalaniFrank W Lee
Oct 29, 2005·Drug Discovery Today·Walter A Korfmacher
Mar 1, 2006·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Xinchun S TongClaude Dufresne
Apr 20, 2006·International Journal of Pharmaceutics·Li DiSusan L Petusky
Oct 20, 2007·Analytical Chemistry·Dietrich A VolmerJay Corr
Aug 5, 2008·Combinatorial Chemistry & High Throughput Screening·Li DiGuy T Carter
Sep 25, 2008·Journal of Biomolecular Screening·Massimiliano FonsiEdith Monteagudo
Jan 1, 2007·Drug Metabolism Letters·Jason S HalladayS Cyrus Khojasteh-Bakht

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Citations

Jul 20, 2011·Journal of the American Chemical Society·Matthew J TraylorDouglas S Clark
Jul 5, 2013·Bioanalysis·Xianmei CaiWilson Z Shou
May 1, 2010·Expert Opinion on Drug Discovery·Raul NicoliDavy Guillarme
May 5, 2012·Trends in Pharmacological Sciences·Tewes Tralau, Andreas Luch
Apr 17, 2012·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Raimo A Ketola, Timo Mauriala
Jan 10, 2012·Rapid Communications in Mass Spectrometry : RCM·Joseph P M HuiJeremy E Melanson
May 15, 2020·Assay and Drug Development Technologies·Johan WernevikThomas Lundböck
Sep 17, 2016·Current Protocols in Pharmacology·Kathleen M KnightsCharles L Crespi
Aug 19, 2021·Drug Metabolism Reviews·Siva Nageswara Rao GajulaRajesh Sonti
Dec 14, 2011·Analytical Chemistry·James HarskampJoanna Y Wilson

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