Final ProgramCPSA 2011
Science and Technology Coming Together to Make a Difference
October 3 - 6, 2011
Bucks County Sheraton Hotel
Langhorne, PA
Poster Abstract #25
Application of a Novel Bench-top Orbitrap Mass Spectrometer with a Quadrupole Mass Filter for Metabolite Profiling in Drug Discovery
1) Bristol-Myers Squibb, Princeton, NJ; 2) Thermo Fisher Scientific, San Jose CA, USA
We present the application of a novel bench-top quadrupole-Orbitrap MS for rapid drug metabolite profiling and identification. For in vitro drug metabolite identification and reactive metabolite screening by LC/MS, a bench-top ion trap MS or comparable low-resolution instruments that can perform polarity switching are routinely employed. The current study investigated the utility of a novel bench-top Orbitrap mass spectrometer equipped with a quadrupole mass filter and a collision cell in fast analysis of metabolic soft spots. This new platform was designed to meet needs for routine metabolite identification tasks by taking key advantages of polarity switching and HR-MS. Timolol, propantheline and rantitidine (10 µM) were incubated in rat liver microsomes (1 mg/mL) fortified with NADPH (1 mM) for 30 min. Metabolites in the incubated samples were analyzed on a Q-Exactive benchtop Oribtrap mass spectrometer. High resolution full scan MS and MS/MS data were collected in a data-dependent fashion with polarity switching. Multiple data mining tools, including mass defect filter (MDF), were employed for metabolite detection. UV responses of metabolites provided semi-quantitative information. HR-MS and MS/MS data acquired in both positive and negative ion modes were utilized for structural elucidation. A number of major and minor metabolites of the model compounds formed in the rat liver microsomal incubations were quickly detected by processing of the accurate MS data using HR-MS data-mining tools. Several metabolites not reported in literature were identified through the analysis. For example, the two metabolites derived from dealkylation of the morpholine moiety of Timolol (P-C2H2 and P-C4H6O) were found in the incubation sample. In addition, polarity switching in one duty cycle of acquisition significantly enhanced metabolite identification capacity. For example, positive and negative MS/MS spectra of Rantitidine metabolites provided different, but complementary structure information of the two major demethylation metabolites, which led to quick identification of the difference in modification positions.
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