Use of Triple Quadrupole–Linear Ion Trap Mass Spectrometry as a Single LC–MS Platform in Drug Metabolism and Pharmacokinetics Studies

Jian, Wenying; Yao, Ming; Wen, Bo; Jones, Elliott; Zhu, Mingshe

doi:10.1002/9780470929278.ch15

Cited by 6 publications

(9 citation statements)

References 71 publications

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“…Like triple quadrupole MS instrument, Qtrap has been widely employed for quantitation of drugs and metabolites in both in vivo pharmacokinetic study and in vitro drug metabolism screening, such as metabolic stability and CYP inhibition assays. The drug metabolite identification capability of Qtrap that is demonstrated in the literature [34] and in the current study allows Qtrap to be used as a single LC/MS platform for quantitative and qualitative analysis in discovery drug metabolism and pharmacokinetics studies.…”

Section: Resultsmentioning

confidence: 81%

“…The hybrid Qtrap instrument is often used as a triple quadrupole instrument for drug and metabolite quantification in drug metabolism and pharmacokinetics studies. On the other hand, its unique scanning functions, including PI scan, NL scan, predictive MRM, and multiple ion monitoring that can trigger MS/MS acquisition, serve well for profiling and identification of drug metabolites and reactive intermediates [34]. There is a new trend that uses a single LC/MS platform in drug metabolism and pharmacokinetics studies in drug discovery, which can significantly reduce cost and increase productivity.…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous Screening of Glutathione and Cyanide Adducts Using Precursor Ion and Neutral Loss Scans-Dependent Product Ion Spectral Acquisition and Data Mining Tools

Jian

Liu²,

Zhao

et al. 2012

J. Am. Soc. Mass Spectrom.

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Drugs can be metabolically activated to soft and hard electrophiles, which are readily trapped by glutathione (GSH) and cyanide (CN), respectively. These adducts are often detected and structurally characterized using separate tandem mass spectrometry methods. We describe a new method for simultaneous screening of GSH and CN adducts using precursor ion (PI) and neutral loss (NL) scansdependent product ion spectral acquisition and data mining tools on an triple quadrupole linear ion trap mass spectrometry. GSH, potassium cyanide, and their stable isotope labeled analogues were incubated with liver microsomes and a test compound. Negative PI scan of m/z 272 for detection of GSH adducts and positive NL scans of 27 and 29 Da for detection of CN adducts were conducted as survey scans to trigger acquisition of enhanced resolution (ER) spectrum and subsequent enhanced product ion (EPI) spectrum. Post-acquisition data mining of EPI data set using NL filters of 129 and 27 Da was then performed to reveal the GSH adducts and CN adducts, respectively. Isotope patterns and EPI spectra of the detected adducts were utilized for identification of their molecular weights and structures. The effectiveness of this method was evaluated by analyzing reactive metabolites of nefazodone formed from rat liver microsomes. In addition to known GSH-and CN-trapped reactive metabolites, several new CN adducts of nefazodone were identified. The results suggested that current approach is highly effective in the analysis of both soft and hard reactive metabolites and can be used as a high-throughput method in drug discovery.

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Section: Resultsmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Simultaneous Screening of Glutathione and Cyanide Adducts Using Precursor Ion and Neutral Loss Scans-Dependent Product Ion Spectral Acquisition and Data Mining Tools

Jian

Liu²,

Zhao

et al. 2012

J. Am. Soc. Mass Spectrom.

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show abstract

“…On account of their high sensitivity, great versatility and general ease of operation, the NL-, PI-, and MRM-dependent MS/MS approaches using the QTRAP have been widely used for fast profiling of stable oxidative metabolites and conjugates, offering product ion spectra with structurally informative fragmentation with no low-mass cutoff (Hopfgartner et al, 2003;Jian et al, 2011;Mauriala et al, 2005;Xia et al, 2003;Yao et al, 2008). In the absence of prior knowledge of fragmentation patterns, multiple ion monitoring (MIM)-EPI was developed for metabolite profiling and characterization (Yao et al, 2008.…”

Section: Data-dependent Ms/ms Acquisition For Drug Metabolite Identifmentioning

confidence: 99%

“…The screening and characterization of reactive metabolites using information-dependent acquisition (IDA) scan functions of the QTRAP are among the instrument's many applications (Jian et al, 2011;Wen & Fitch, 2009a,b). Characteristic fragmentation of GSH conjugates has been extensively investigated as described above (Baillie & Davis, 1993;Haroldsen et al, 1988;Pearson et al, 1990) and, similar to the CID of peptides, fragmentation of GSH conjugates is mainly a result of cleavage of the peptide backbone of the GSH moiety in the positive mode.…”

Section: Data-dependent Ms/ms Acquisition For Drug Metabolite Identifmentioning

confidence: 99%

Applications of mass spectrometry in drug metabolism: 50 years of progress

Wen

Zhu

2015

Drug Metabolism Reviews

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109

102

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Mass spectrometry plays a pivotal role in drug metabolism studies, which are an integral part of drug discovery and development nowadays. Metabolite identification has become critical to understanding the metabolic fate of drug candidates and to aid lead optimization with improved metabolic stability, toxicology and efficacy profiles. Ever since the introduction of atmospheric ionization techniques in the early 1990s, liquid chromatography coupled with mass spectrometry (LC/MS) has secured a central role as the predominant analytical platform for metabolite identification as LC and MS technologies continually advanced. In this review, we discuss the evolution of both MS technology and its applications over the past 50 years to meet the increasing demand of drug metabolism studies. These advances include ionization sources, mass analyzers, a wide range of MS acquisition strategies and data mining tools that have substantially accelerated the metabolite identification process and changed the overall drug metabolism landscape. Exemplary applications for characterization and identification of both small-molecule xenobiotics and biological macromolecules are described. In addition, this review discusses novel MS technologies and applications, including xenobiotic metabolomics that hold additional promise for advancing drug metabolism research, and offers thoughts on remaining challenges in studying the metabolism and disposition of drugs and other xenobiotics.

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“…The triple quadrupole -linear ion trap instrument is capable of performing quantitative analysis using SRM as well as metabolite identifi cation using PI -, NL -, MRM -, and MIM -dependent EPI acquisition. It is an ideal LC -MS platform for a bioanalytical or in vitro ADME lab where quantitative analysis is the major task and metabolite identifi cation experiment is occasionally carried out [188] . HR -MS is another type of LC -MS platform that enables both metabolite identifi cation and quantitative analysis of drugs.…”

Section: Summary and Perspectivementioning

confidence: 99%

LC‐MS in Drug Metabolism and Pharmacokinetics: A Pharmaceutical Industry Perspective

Jian

Shou

Edom

et al. 2012

Mass Spectrometry Handbook

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Use of Triple Quadrupole–Linear Ion Trap Mass Spectrometry as a Single LC–MS Platform in Drug Metabolism and Pharmacokinetics Studies

Cited by 6 publications

References 71 publications

Simultaneous Screening of Glutathione and Cyanide Adducts Using Precursor Ion and Neutral Loss Scans-Dependent Product Ion Spectral Acquisition and Data Mining Tools

Simultaneous Screening of Glutathione and Cyanide Adducts Using Precursor Ion and Neutral Loss Scans-Dependent Product Ion Spectral Acquisition and Data Mining Tools

Applications of mass spectrometry in drug metabolism: 50 years of progress

LC‐MS in Drug Metabolism and Pharmacokinetics: A Pharmaceutical Industry Perspective

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