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Rapid CommunicationShort Communication

Ion Mobility Spectrometry–Mass Spectrometry Analysis for the Site of Aromatic Hydroxylation

Atsushi Shimizu and Masato Chiba
Drug Metabolism and Disposition July 2013, 41 (7) 1295-1299; DOI: https://doi.org/10.1124/dmd.113.051953
Atsushi Shimizu
Discovery Drug Metabolism & Pharmacokinetics, Pharmacokinetics Research Laboratories, Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Ibaraki, Japan
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Masato Chiba
Discovery Drug Metabolism & Pharmacokinetics, Pharmacokinetics Research Laboratories, Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Ibaraki, Japan
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Abstract

Hydroxylated metabolites often retain the pharmacological activity of parent compound, and the position of hydroxylation determines the formation of chemically reactive intermediates, such as quinones and analogs, from para- and/or ortho-hydroxylation of phenols or arylamines. Therefore, the identification of exact position of hydroxylation is often required at the early development stage of new drug candidates. In many cases, liquid chromatography–tandem mass spectrometry (LC-MS/MS) provides identical MS/MS spectra among isomeric hydroxylated metabolites, and therefore, it alone cannot unequivocally identify the exact position(s) of hydroxylation. Ion mobility spectrometry (IMS), integrated with LC-MS/MS, recently showed the capability of separating isomeric species based on differences in their drift times from IMS, which are linearly proportional to the collision cross-section (CCS) reflecting physical size and shape. In the present study, a chemical derivatization of isomeric hydroxylated metabolites with 2-fluoro-N-methyl pyridinium p-toluenesulfonate was found to confer distinct theoretical CCS value on each isomer by forming corresponding N-methyl pyridine (NMP) derivative. The regression lines established by the comparison between theoretical CCS values and observed drift times from IMS for each set of parent compound (labetalol, ezetimibe, atorvastatin, and warfarin) and its MS/MS product ions accurately and selectively projected the actual drift times of NMP derivatives of corresponding aromatic or isomeric hydroxylated metabolites. The established method was used for the accurate assignment of predominant formation of 2-hydroxylated metabolite from imipramine in NADPH- fortified human liver microsomes. The present application expands the versatility of LC-IMS-MS technique to the structure identification of isomeric hydroxylated metabolites at the early stage for drug development.

Footnotes

    • Received March 14, 2013.
    • Accepted April 8, 2013.
  • dx.doi.org/10.1124/dmd.113.051953.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (7)
Drug Metabolism and Disposition
Vol. 41, Issue 7
1 Jul 2013
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Rapid CommunicationShort Communication

Ion Mobility Site Identification of Hydroxylated Metabolites

Atsushi Shimizu and Masato Chiba
Drug Metabolism and Disposition July 1, 2013, 41 (7) 1295-1299; DOI: https://doi.org/10.1124/dmd.113.051953

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Rapid CommunicationShort Communication

Ion Mobility Site Identification of Hydroxylated Metabolites

Atsushi Shimizu and Masato Chiba
Drug Metabolism and Disposition July 1, 2013, 41 (7) 1295-1299; DOI: https://doi.org/10.1124/dmd.113.051953
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