CPSA 2011

Science and Technology Coming Together to Make a Difference

October 3 - 6, 2011
Bucks County Sheraton Hotel
Langhorne, PA

Program Abstract

Tuesday, Metabolite Identification Session

Streamlining the Drug Discovery Biotransformation Workflow: HRMS with on-the-fly-MDF and NL and the application of Metabolite Pilot™ Software

Xiaomei Gu, Hong Cai, Ramaswamy Iyer, W. Griffith Humphreys, and Ragu Ramanathan
Bristol-Myers Squibb

Metabolite detection and structure elucidation is the crucial step of biotransformation studies in drug discovery and development process. Traditionally, this process has been conducted with unit resolution mass spectrometers followed by time consuming and labor intensive manual interpretation of mass spectra. In recent years, there has been a shift toward high resolution mass spectrometry (HRMS) based accurate mass measurements. The availability of elemental composition for a precursor ion and its fragment ions in spectra has greatly enhanced the confidence in software facilitated structure assignment, and metabolic transformation of drug candidates. Additionally, combining accurate mass measurements and the mass defect filter (MDF) have significantly reduced the false positive in metabolite identification and increase the throughput. However, until recently, MDF technique and neutral loss scan were mainly used for post-acquisition processing of data acquired using HRMS mass spectrometers. Recently introduced multiple mass defect triggered IDA (Information Dependent Acquisition) improved efficiency and reduces the need for multiple injections to get comprehensive metabolism information. In addition, neutral loss (NL) triggered IDA provides unique specificity by triggering MS/MS when two TOF-MS/MS scans (high and low energy) detect a specific accurate mass difference. Both positive and negative ionization modes were utilized to explore with NL scan to detect reactive metabolite. The result is more efficient IDA experiments with fewer runs and repeat injections. Metabolite PilotTM software automatically predicted some of the potential cleavage metabolites based on the parent compound structure, calculated MDF for phase I, II metabolites, parent compound, as well as potential cleavage metabolites. Metabolite PilotTM also allowed the application of multiple MDF, isotope pattern based metabolite search, and metabolite search based on common product ions or neutral loss simultaneously to streamline the overall metabolite identification workflow.

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