Published In

Journal of Electroanalytical Chemistry

Document Type

Post-Print

Publication Date

1-2016

Subjects

Electrochemistry, Azoles, Metabolites, Mass spectrometry, Thyroid antagonists, Biotransformation (Metabolism)

Abstract

Methimazole (MMI), an antithyroid drug, is associated with idiosyncratic toxicity. Reactive metabolites resulting from bioactivation of the drug have been implicated in these adverse drug reactions. Mimicry of enzymatic oxidation of MMI was carried out by electrochemically oxidizing MMI using a coulometric flow-through cell equipped with a porous graphite working electrode. The cell was coupled on-line to electrospray ionization mass spectrometry (EC/ESI-MS). ESI spectra were acquired in both negative and positive modes. In acidic medium, ESI spectral analysis showed that the dimer was the main product, while in neutral and basic media, methimazole sulfenic acid, methimazole sulfinic acid and methimazole sulfonic acid were observed as the major electrochemical oxidation products. Oxidation of MMI and subsequent trapping with nucleophiles resulted in formation of adducts with N-acetylcysteine. Some of the electrochemically generated species observed in these experiments were similar to metabolites that have been observed from in vitro and in vivo studies. Trapping studies also showed that bioactivation of MMI proceeds predominantly through the S-oxide and not through formation of thiyl radicals. These results show that electrochemistry coupled to mass spectrometry can be used in mimicry of oxidative metabolism and subsequent high throughput screening of metabolites.

Description

This is the author’s version of a work that was accepted for publication. The definitive version can be found at the publishers site.

This work is licensed under a Creative Commons Attribution 4.0 International License.

DOI

10.1016/j.jelechem.2015.10.041

Persistent Identifier

http://archives.pdx.edu/ds/psu/17708

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