Adverse drug reactions caused by toxic drug metabolites are one of the major reasons for drugs being withdrawn from the market. Therefore, identifying the structures of drug metabolites is required at the early stages of drug development. However, detecting and identifying metabolites that are present at low concentrations in complex mixtures poses a great challenge. Glucuronidation is a major pathway in drug metabolism within the human body. Whether drugs form glucuronides at either N- or O- atoms affect the pharmacological, toxicological and/or pharmacokinetic profiles of the metabolite. Therefore, being able to quickly identify the structures of these metabolites would greatly benefit drug development and adverse drug reaction studies. Tandem mass spectrometry is an invaluable tool in identification of minor mixture components, which is usually based on dissociation reactions of ionized analytes. However, the use of gas-phase ion/molecule reactions to identify specific functionalities in ionized analytes is much more reliable. In this work, deprotonated N- and O-glucuronides were isolated and allowed to react with trichlorosilane in a linear quadruple ion trap mass spectrometer. Formation of diagnostic product ions enabled unambiguous identification of isomeric N- and O-glucuronidated drugs. Feasible reaction mechanisms were explored by quantum chemical calculations. This method of using gas-phase ion/molecule reactions enables high throughput functional group identification without purification of the metabolites, which has proven to be effective in identification of trace amounts of drug metabolites in complex mixtures.

Differentiating isomeric glucuronide drug metabolites via gas phase ion/molecule reactions

255th National Meeting (2018)

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