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Detection of glutathione conjugates of amiodarone and its reactive diquinone metabolites in rat bile using mass spectrometry tools.

RATIONALE
Amiodarone is reported to cause hepato and pulmonary toxicity in humans, which has been envisaged to be due to formation of its reactive metabolites, essentially based on its structural similarity to benzbromarone, a drug withdrawn from the market due to reasons of similar hepatotoxicity. Therefore, the purpose of this study was to detect glutathione conjugates of amiodarone and its reactive diquinone metabolites in rat bile using mass spectrometry tools.


METHODS
Wistar rats were dosed orally with an amiodarone suspension and bile was collected via bile duct cannulation followed by solid-phase extraction, protein precipitation and centrifugation. Samples were analysed by liquid chromatography coupled with linear ion trap mass spectrometry using tandem mass and constant neutral loss scan in positive electrospray ionization mode.


RESULTS
Glutathione adducts of amiodarone and its reactive diquinone metabolites were identified and characterized with the characteristic neutral loss of 129 Da. Glucuronide conjugates of previously reported stable phase-1 metabolites were also observed.


CONCLUSIONS
This study confirmed generation of reactive metabolites of amiodarone for the first time, as was hypothesised earlier by various research groups. Also, the responsible toxicophore was identified to be a benzofuran moiety liable to form reactive diquinone species. However, the results need to be further confirmed in human subjects. Copyright © 2016 John Wiley & Sons, Ltd.