Abstract
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.
Highlights
The conventional method of studying oxidative drug metabolism during preclinical experiments is through animal models or perfused organs in vitro.[1]
Members of the cytochromes P450 class (CYP450) of enzymes are responsible for the majority of phase I biotransformations leading to reactive electrophilic intermediates.[7]
Jurva and co-workers investigated the extent to which this technique could be used to mimic cytochrome P450 catalyzed reactions by comparing metabolites generated from EC/LC/MS to those that were generated from the P450 system
Summary
The conventional method of studying oxidative drug metabolism during preclinical experiments is through animal models (in vivo) or perfused organs in vitro.[1]. It remains a challenge to extrapolate data generated from such systems to actual In vivo systems, these biomimetic tools offer some advantages that are not inherent in conventional methods. Jurva and co-workers investigated the extent to which this technique could be used to mimic cytochrome P450 catalyzed reactions by comparing metabolites generated from EC/LC/MS to those that were generated from the P450 system. Their results showed that reactions such as N-dealkylation, S-oxidation, P-oxidation, alcohol oxidation and dehydrogenation that proceed via a mechanism initiated by one-electron oxidation or hydrogen abstraction are amenable to electrochemical oxidation.[8]
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