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Research ArticleArticle

A Simple Liquid Chromatography-Tandem Mass Spectrometry Method to Determine Relative Plasma Exposures of Drug Metabolites across Species for Metabolite Safety Assessments (Metabolites in Safety Testing). II. Application to Unstable Metabolites

Hongying Gao and R. Scott Obach
Drug Metabolism and Disposition July 2012, 40 (7) 1290-1296; DOI: https://doi.org/10.1124/dmd.112.044552
Hongying Gao
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R. Scott Obach
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Abstract

We previously described a simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine relative plasma exposures of drug metabolites across species for metabolite safety assessments. It offers time- and resource-sparing advantages to ascertain metabolite exposure comparisons between humans and laboratory animal species for stable metabolites with high confidence. In this study, we tested the limitation of the methodology with compounds possessing six substituents found in unstable metabolites. Stabilization procedures were used, and stabilized samples were compared with untreated samples for structures with established stabilization processes. In most cases, the parent compounds with established stability were used as the intrinsic stability references except in cases in which the metabolite was more stable than the parent compound. Long-term storage stability of the unstable structures was tested by comparing the response ratio of the metabolite to the stability reference compound for multiple independent analyses covering the storage duration. Autosampler stability was tested using the same response ratio of the reinjections of the reconstituted solution overnight over the first injections. The results supported that the possibility that an abbreviated LC-MS/MS peak area ratio comparison can be applied to epoxide, amide, catechol, and acyl glucuronides to determine the relative plasma exposure of drug metabolites across species; but it may not be suitable for iminium ions and esters. Stability of suspected unstable metabolites can be tested using the methodology described above.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.112.044552.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    HPLC
    high-performance liquid chromatography
    MS
    mass spectrometry
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    IS
    internal standard
    MRM
    multiple reaction monitoring
    MIM
    multiple ion monitoring
    EPI
    enhanced production.

  • Received January 10, 2012.
  • Accepted March 27, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (7)
Drug Metabolism and Disposition
Vol. 40, Issue 7
1 Jul 2012
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Research ArticleArticle

LC-MS/MS FOR SAFETY ASSESSMENTS OF UNSTABLE METABOLITES

Hongying Gao and R. Scott Obach
Drug Metabolism and Disposition July 1, 2012, 40 (7) 1290-1296; DOI: https://doi.org/10.1124/dmd.112.044552

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Research ArticleArticle

LC-MS/MS FOR SAFETY ASSESSMENTS OF UNSTABLE METABOLITES

Hongying Gao and R. Scott Obach
Drug Metabolism and Disposition July 1, 2012, 40 (7) 1290-1296; DOI: https://doi.org/10.1124/dmd.112.044552
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