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Rapid CommunicationShort Communication

A Novel Method for the Determination of the Site of Glucuronidation by Ion Mobility Spectrometry-Mass Spectrometry

Atsushi Shimizu, Tomoyuki Ohe and Masato Chiba
Drug Metabolism and Disposition August 2012, 40 (8) 1456-1459; DOI: https://doi.org/10.1124/dmd.112.045435
Atsushi Shimizu
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Tomoyuki Ohe
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Masato Chiba
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Abstract

Glucuronidation not only plays a detoxifying role in living body, but it also can complicate pharmacological and toxicological profiles of new drug candidates by forming active and reactive conjugated metabolites. The opportunity to elucidate structure of conjugated metabolites has increased in drug metabolism studies at the early development stage. General methodologies for the structure elucidation of glucuronide conjugate(s) include liquid chromatography-tandem mass spectrometry (LC-MS/MS) and NMR spectroscopy. In many cases, LC-MS/MS alone cannot unequivocally identify the site(s) of conjugation in isomeric glucuronidations. In the present study, we established a new strategy for the structure elucidation of glucuronide conjugates using ion mobility spectrometry (IMS)-mass spectrometry. Linear correlation between calculated collision cross-sections (CCS) and actual drift times from IMS was found for each set of parent compound (raloxifene, losartan, telmisartan, and estradiol) and the corresponding MS/MS product ions. Thus, obtained regression lines accurately and selectively projected the actual drift times of authentic standards of glucuronide conjugate based on the theoretical CCS values. The established method was used for the accurate assignment of predominant formation of phenolic glucuronide conjugate (SCH 60663) in the isomeric (phenolic and benzylic) glucuronidations of ezetimibe in the incubated sample with cryopreserved human hepatocytes. This application demonstrates the potential to facilitate the structure identification of glucuronide conjugates at the early development stage of new drug candidates.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.045435.

  • ABBREVIATIONS:

    UGT
    UDP-glucuronosyltransferase
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    IMS
    ion mobility spectrometry
    CCS
    collision cross-section
    MS
    mass spectrometry
    3D
    three dimensional
    UPLC
    ultraperformance liquid chromatography
    TM
    trajectory method
    SCH 60663
    ezetimibe phenoxyglucuronide.

  • Received March 1, 2012.
  • Accepted May 18, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (8)
Drug Metabolism and Disposition
Vol. 40, Issue 8
1 Aug 2012
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Rapid CommunicationShort Communication

IDENTIFICATION OF GLUCURONIDATION SITES BY ION MOBILITY

Atsushi Shimizu, Tomoyuki Ohe and Masato Chiba
Drug Metabolism and Disposition August 1, 2012, 40 (8) 1456-1459; DOI: https://doi.org/10.1124/dmd.112.045435

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Rapid CommunicationShort Communication

IDENTIFICATION OF GLUCURONIDATION SITES BY ION MOBILITY

Atsushi Shimizu, Tomoyuki Ohe and Masato Chiba
Drug Metabolism and Disposition August 1, 2012, 40 (8) 1456-1459; DOI: https://doi.org/10.1124/dmd.112.045435
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