A High Throughput LC/MS/MS Method for Screening Glutathione Conjugations using Exact Mass Neutral Loss

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Waters Poster Reprint
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Over the years, reactive metabolites are believed to have played an important role in the safety profile of pharmaceuticals. Chemically reactive metabolites of a drug can bind to proteins or DNA which is postulated to result in various direct and idiosynchratic toxicities. Therefore, this represents a key target for early screening to help prevent compound failure at a later stage. In order to address this issue, an assay has been developed to detect the formation of reactive metabolites by using LC/MS/MS with exact mass measurement to search for metabolites conjugated with glutathione from in-vitro incubations. Until recently, this work has been carried out with triple quadrupole technology using nominal mass. The advantage of the hybrid quadrupole time of flight mass spectrometer is the selectivity and sensitivity that can be achieved with it. In this presentation, we will present data to substantiate this approach and also how exact mass measurement can help to identify and postulate putative metabolites.The test substrates used herein were acetaminophen, troglitazone and raloxifene.

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