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P1013
A Rapid Assay for p450 Inhibition/Induction Utilizing Ultra Performance Liquid Chromatography & Tandem Quadrupole Mass Spectrometry
Presenter Paul Rainville, Waters Corporation
Additional Authors: Jessalynn P. Weaton, Peter G. Alden, and Robert S. Plumb
A significant number of candidate medicines fall out of the development process due to toxicity. The later this occurs in the discovery/development process the more costly it becomes. A number of high profile medicines have been withdrawn from the market due to toxic events. These clinical events are often due to drug-drug interaction or unpredictable “idiosyncratic” events. As part of the drug discovery and development process it is critical to evaluate the candidate drugs for possible toxicity / drug-drug interactions or inhibition/induction of metabolizing enzymes in the body. Failure to properly identify these potential toxic events can lead the compound being withdrawn from the market and a significant loss in revenue. The effect of a candidate medicine on the major drug metabolizing enzymes, Cytochrome p450 (CYP450) is studied in both discovery as part of the lead candidate evaluation process and during development to determine potential drug-drug interactions. These studies involve evaluating the effect of the candidate medicine on the drug metabolizing CYP450 enzymes by monitoring the changes in the concentrations on a set of probe substrate molecules. These assays are typically performed by HPLC/UV or more recently by LC/MS/MS with analysis times in the 5-10 minute range. Recent advances in the manufacture of sub 2µm chromatographic particles have led to improved performance and faster analysis over traditional LC. Here we show the application of sub 2 µm chromatographic particles coupled with tandem mass spectrometry for the analysis of six CYP450 metabolites within 30 seconds.