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LC-MS/MS Based Detection and Characterization of Covalent Glutathione Modifications Formed by Reactive Drug of Abuse Metabolites

NCJ Number
Date Published
13 pages
This study utilized a metabolic assay with the tripeptide glutathione (GSH) as a nucleophilic trapping agent to bind reactive drug metabolites formed in situ.
Conjugation with the tripeptide glutathione (GSH) is a common mechanism of detoxification of many endogenous and exogenous compounds. This phenomenon typically occurs through the formation of a covalent bond between the nucleophilic free thiol moiety of GSH and an electrophilic site on the compound of interest. Although GSH adducts have been identified for many licit drugs, there is a lack of information on the ability of drugs of abuse to adduct GSH. The current study collected extracted ion MS spectra via LC-QqQ-MS/MS for all potentially significant ions and examined for fragmentation common to GSH-containing compounds, followed by confirmation of adduction and structural characterization performed by LC-QTOF-MS/MS. In addition to the two positive controls, of the 14 drugs of abuse tested, 10 exhibited GSH adduction, with several forming multiple adducts, resulting in a total of 22 individual identified adducts. A number of these are previously unreported in the literature, including those for diazepam, naltrexone, oxycodone and Ä9-THC. (publisher abstract modified)

Date Published: January 1, 2019