Application of LC-high-resolution MS with “intelligent” data mining tools for screening reactive Drug metabolites

Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA.
Bioanalysis (Impact Factor: 3). 03/2012; 4(5):501-10. DOI: 10.4155/bio.12.5
Source: PubMed


Biotransformation of chemically stable compounds to reactive metabolites that can bind covalently to macromolecules (such as proteins and DNA) is considered an undesirable property of drug candidates. Due to the possible link, which has not yet been conclusively demonstrated, between reactive metabolites and adverse drug reactions, screening for metabolic activation of lead compounds through in vitro chemical trapping experiments has become an integral part of the drug discovery process in many laboratories. In this review, we provide an overview of the recent advances in the application of high-resolution MS. These advances facilitated the development of accurate-mass-based data mining tools for high-throughput screening of reactive drug metabolites in drug discovery.

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    ABSTRACT: This chapter contains sections titled: Introduction In Vitro Trapping of Reactive Metabolites Traditional Liquid Chromatography-Tandem Mass Spectrometry (LC/MS/MS) Approaches for Reactive Metabolite Screening HRMS Accurate Mass-Based Data Mining Tools for Screening Reactive Metabolites Quantitation of Reactive Metabolite Formation Challenges and Future Perspectives References
    Mass Spectrometry for Drug Discovery and Drug Development, 01/2013: pages 339-355; , ISBN: 9780470942383
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    ABSTRACT: Effective characterization of drug metabolites in complex biological matrices is facilitated by mass spectrometers with high resolving power, mass accuracy and sensitivity. This review begins with an overview of high-resolution MS terminology and the different types of instrumentation that are currently available. Metabolite structure analysis offers unique challenges and, therefore, the different types of approaches used to solve problems are highlighted through specific examples. Overall, this review describes the value that high-resolution MS brings to drug-metabolism studies.
    Bioanalysis 02/2013; 5(4):463-79. DOI:10.4155/bio.13.3 · 3.00 Impact Factor
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    ABSTRACT: High-resolution MS (HRMS) in conjunction with LC (LC-HRMS) has become available to many laboratories in the pharmaceutical industry. Due to its enhanced, though sometime perceived, specificity using the high-resolution power and its capability of simultaneous quantitation and structural elucidation using the post-acquisition data mining feature, utilization of LC-HRMS for bioanalysis could lead to potential rapid and reliable method development as well as sample analysis, thus generating both cost and resource savings. Here, we would like to share our perspectives about several current and future applications of LC-HRMS in bioanalysis. We will also discuss the factors influencing the quality of method establishment and potential pitfalls that need to be considered for the utilization of LC-HRMS in the field of regulated bioanalysis. We believe when utilized appropriately, LC-HRMS will play a significant role in the future landscape of quantitative bioanalysis.
    Bioanalysis 05/2013; 5(10):1269-76. DOI:10.4155/bio.13.100 · 3.00 Impact Factor
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