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A high throughput strategy is essential in accelerating the lead optimization phase in the drug development cycle. The strategy discussed here involves the simultaneous determination of the nature and extent of metabolism by performing metabolite identification and metabolic stability measurements in a single analytical run. Using the LTQ, the increased throughput gains are achieved without sacrificing data quality.
The combination of ultra-fast cycle time and high spectral quality on the LTQ are key to achieving a balance between speed and spectral quality. An automated five scan event LC-MSn method including MS , MS /MS and MS3 scans with automated Data Dependent acquisition was utilized. The full scan MS data points were used to determine metabolic stability, whereas the MS/MS and MS3 scan were used for structural characterization of the metabolites. These experiments were performed on a set of 8 drugs with low, intermediate and fast metabolic rates. The ultra-fast cycle time of the LTQ enables acquisition of enough data points across the LC peak for accurate measurement of metabolic stability even under ultra-fast chromatographic conditions. Additionally, the high sensitivity and MSn spectral quality provides confident identification and characterization of co-eluting metabolites. This presentation highlights the ability of the LTQ to provide more information with less sample and in less time.
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| The Data Dependent Experiment |
This high throughput strategy for determining the rate of metabolism and screening for potentially toxic metabolites can provide faster feedback to guide synthesis efforts, and to optimize PK and safety characteristics of drug candidates. This in turn helps accelerate the drug development process which can lead to speed to market and reduced development costs.
The following webinar discusses this strategy further:
Title: Simultaneous Metabolite Identification and Metabolic Stability on the LTQ Linear Ion Trap
Speakers: Gargi Choudhary , Diane Cho
View Recording Now!!
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