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Cyanide Trapping of Iminium Ion Reactive Intermediates Followed by Detection and Structure Identification Using Liquid Chromatography−Tandem Mass Spectrometry (LC-MS/MS)

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The Barnett Institute and Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, and Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406
Cite this: Chem. Res. Toxicol. 2005, 18, 10, 1537–1544
Publication Date (Web):September 22, 2005
Copyright © 2005 American Chemical Society

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    Secondary and tertiary alicyclic amines are widely found in pharmaceuticals and environmental compounds. The formation of iminium ions as reactive intermediates in the metabolic activation of alicyclic amines has previously been investigated in radiometric assays where radiolabeled cyanide is typically employed. In this paper, we report a relatively high throughput LC-MS/MS method for the detection of the nonradiolabeled cyanide adduct formed in rat or human liver microsomal incubations via constant neutral loss scan followed by structural characterization using product ion scan on a triple quadrupole mass spectrometer. A total of 14 alicyclic amine compounds were investigated with the cyanide trapping LC-MS/MS screen and also with the glutathione (GSH) trapping screen, a well-established and commonly employed technique for reactive metabolite screening. Our results are found to be in general agreement with the previous metabolism reports for these compounds, demonstrating the effectiveness, speed, and simplicity of the cyanide trapping LC-MS/MS method to study the iminium ion intermediates from alicyclic amines and its complementarities to GSH trapping method for reactive metabolite screenings.

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     Northeastern University.

     GlaxoSmithKline Pharmaceuticals.


     Corresponding author. Tel, 610-270-6291; fax, 610-270-4971; e-mail, [email protected].

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