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High-throughput liquid chromatography/mass spectrometry method for the quantitation of small molecules using accurate mass technologies in supporting discovery drug screening.
MedLine Citation:
PMID:  23280971     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
RATIONALE: Drug discovery samples are routinely analyzed using liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods on triple quadrupole mass spectrometers employing multiple reaction monitoring (MRM). In order to improve analysis throughput, quantitation of small molecules on a quadrupole time-of-flight (QqTOF) instrument using TOF scan and high-resolution MRM (MRM-HR) modes was evaluated in this study.
METHODS: Cassette dosed plasma and brain samples from nine compounds were extracted using a protein precipitation method. Separation was achieved by reversed-phase liquid chromatography. Mass spectrometric analysis was performed using TOF scan and high-resolution MRM approaches on a QqTOF mass spectrometer with turbo-ionspray ionization. Results were compared to those obtained on a triple quadrupole mass spectrometer.
RESULTS: The dynamic range varied depending on compounds and instruments and was similar between the MRM on QqQ and full TOF scan mode on QqTOF. Linear or quadratic regression and 1/x(2) weighting were used. Resolution on the QqTOF instrument was around 32000 and mass accuracy was within 4.4 ppm. The MRM-HR method showed better sensitivity compared to the TOF scan method, and was comparable to the MRM on a QqQ mass spectrometer. Assay accuracy was within ±25%.
CONCLUSIONS: A TOF scan method allowed the use of the generic method without compound-specific optimization and was an alternative choice for routine high-throughput quantitation of small molecules. The MRM-HR method on the QqTOF showed good sensitivity which was comparable to that obtained by the MRM method on the triple quadrupole mass spectrometer. Copyright © 2012 John Wiley & Sons, Ltd.
Authors:
Xiao Ding; Hesham Ghobarah; Xiaolin Zhang; Allan Jaochico; Xingrong Liu; Gauri Deshmukh; Bianca M Liederer; Cornelis E C A Hop; Brian Dean
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Rapid communications in mass spectrometry : RCM     Volume:  27     ISSN:  1097-0231     ISO Abbreviation:  Rapid Commun. Mass Spectrom.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-02     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8802365     Medline TA:  Rapid Commun Mass Spectrom     Country:  England    
Other Details:
Languages:  eng     Pagination:  401-8     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 John Wiley & Sons, Ltd.
Affiliation:
Genentech, Inc., Drug Metabolism and Pharmacokinetics, MS 412A, 1 DNA Way, South San Francisco, CA 94080, USA. ding.xiao@gene.com.
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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