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Research ArticleArticle

High-Resolution Mass Spectrometry Elucidates Metabonate (False Metabolite) Formation from Alkylamine Drugs during In Vitro Metabolite Profiling

Joanna E. Barbara, Faraz Kazmi, Seema Muranjan, Paul C. Toren and Andrew Parkinson
Drug Metabolism and Disposition October 2012, 40 (10) 1966-1975; DOI: https://doi.org/10.1124/dmd.112.047027
Joanna E. Barbara
XenoTech, LLC, Lenexa, Kansas (J.E.B., F.K., S.M., P.C.T.); and XPD Consulting, Shawnee, Kansas (A.P.)
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Faraz Kazmi
XenoTech, LLC, Lenexa, Kansas (J.E.B., F.K., S.M., P.C.T.); and XPD Consulting, Shawnee, Kansas (A.P.)
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Seema Muranjan
XenoTech, LLC, Lenexa, Kansas (J.E.B., F.K., S.M., P.C.T.); and XPD Consulting, Shawnee, Kansas (A.P.)
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Paul C. Toren
XenoTech, LLC, Lenexa, Kansas (J.E.B., F.K., S.M., P.C.T.); and XPD Consulting, Shawnee, Kansas (A.P.)
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Andrew Parkinson
XenoTech, LLC, Lenexa, Kansas (J.E.B., F.K., S.M., P.C.T.); and XPD Consulting, Shawnee, Kansas (A.P.)
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Abstract

In vitro metabolite profiling and characterization experiments are widely employed in early drug development to support safety studies. Samples from incubations of investigational drugs with liver microsomes or hepatocytes are commonly analyzed by liquid chromatography/mass spectrometry for detection and structural elucidation of metabolites. Advanced mass spectrometers with accurate mass capabilities are becoming increasingly popular for characterization of drugs and metabolites, spurring changes in the routine workflows applied. In the present study, using a generic full-scan high-resolution data acquisition approach with a time-of-flight mass spectrometer combined with postacquisition data mining, we detected and characterized metabonates (false metabolites) in microsomal incubations of several alkylamine drugs. If a targeted approach to mass spectrometric detection (without full-scan acquisition and appropriate data mining) were employed, the metabonates may not have been detected, hence their formation underappreciated. In the absence of accurate mass data, the metabonate formation would have been incorrectly characterized because the detected metabonates manifested as direct cyanide-trapped conjugates or as cyanide-trapped metabolites formed from the parent drugs by the addition of 14 Da, the mass shift commonly associated with oxidation to yield a carbonyl. This study demonstrates that high-resolution mass spectrometry and the associated workflow is very useful for the detection and characterization of unpredicted sample components and that accurate mass data were critical to assignment of the correct metabonate structures. In addition, for drugs containing an alkylamine moiety, the results suggest that multiple negative controls and chemical trapping agents may be necessary to correctly interpret the results of in vitro experiments.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.112.047027.

  • ABBREVIATIONS:

    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    MS
    mass spectrometry
    ToF
    time of flight
    UHPLC
    ultra-high-pressure liquid chromatography
    MSE
    elevated energy mass spectrometry
    HLM
    human liver microsomes
    HIM
    human intestinal microsomes
    LC/MSE
    liquid chromatography/elevated energy mass spectrometry
    ESI
    electrospray ionization
    NL
    neutral loss.

  • Received June 6, 2012.
  • Accepted July 13, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (10)
Drug Metabolism and Disposition
Vol. 40, Issue 10
1 Oct 2012
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Research ArticleArticle

IN VITRO METABONATE FORMATION FROM ALKYLAMINES

Joanna E. Barbara, Faraz Kazmi, Seema Muranjan, Paul C. Toren and Andrew Parkinson
Drug Metabolism and Disposition October 1, 2012, 40 (10) 1966-1975; DOI: https://doi.org/10.1124/dmd.112.047027

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Research ArticleArticle

IN VITRO METABONATE FORMATION FROM ALKYLAMINES

Joanna E. Barbara, Faraz Kazmi, Seema Muranjan, Paul C. Toren and Andrew Parkinson
Drug Metabolism and Disposition October 1, 2012, 40 (10) 1966-1975; DOI: https://doi.org/10.1124/dmd.112.047027
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