High-throughput, accurate mass liquid chromatography/tandem mass spectrometry on a quadrupole time-of-flight system as a 'first-line' approach for metabolite identification studies.

Throughput for drug metabolite identification studies has been increased significantly by the combined use of accurate mass liquid chromatography/tandem mass spectrometry (LC/MS/MS) data on a quadrupole time-of-flight (QTOF) system and targeted data analysis procedures. Employed in concert, these tools have led to the implementation of a semi-automated high-throughput metabolite identification strategy that has been incorporated successfully into lead optimization efforts in drug discovery. The availability of elemental composition data on precursor and all fragment ions in each spectrum has greatly enhanced confidence in ion structure assignments, while computer-based algorithms for defining sites of biotransformation based upon mass shifts of diagnostic fragment ions have facilitated identification of positions of metabolic transformation in drug candidates. Adoption of this technology as the 'first-line' approach for in vitro metabolite profiling has resulted in the analysis of as many as 21 new chemical entities on one day from diverse structural classes and therapeutic programs.

[1]  R. Mortishire-Smith,et al.  Automated assignment of high‐resolution collisionally activated dissociation mass spectra using a systematic bond disconnection approach , 2005 .

[2]  Jennifer H Granger,et al.  Increasing throughput and information content for in vitro drug metabolism experiments using ultra-performance liquid chromatography coupled to a quadrupole time-of-flight mass spectrometer. , 2005, Rapid communications in mass spectrometry : RCM.

[3]  Angus Nedderman,et al.  Analytical strategies for identifying drug metabolites. , 2007, Mass spectrometry reviews.

[4]  Mark Wrona,et al.  MSE with mass defect filtering for in vitro and in vivo metabolite identification. , 2007, Rapid communications in mass spectrometry : RCM.

[5]  R. Kostiainen,et al.  Feasibility of different mass spectrometric techniques and programs for automated metabolite profiling of tramadol in human urine. , 2006, Rapid communications in mass spectrometry : RCM.

[6]  A. P. Land,et al.  Application of liquid chromatography-mass spectrometry(n) analyses to the characterization of novel glyburide metabolites formed in vitro. , 1998, Journal of chromatography. A.

[7]  Nicola C Hughes,et al.  Accurate mass measurement at enhanced mass-resolution on a triple quadrupole mass-spectrometer for the identification of a reaction impurity and collisionally-induced fragment ions of cabergoline. , 2003, Rapid communications in mass spectrometry : RCM.

[8]  R. Plumb,et al.  Investigating the human metabolism of acetaminophen using UPLC and exact mass oa-TOF MS. , 2005, Journal of pharmaceutical and biomedical analysis.

[9]  Desmond O'Connor,et al.  Accelerated throughput metabolic route screening in early drug discovery using high-resolution liquid chromatography/quadrupole time-of-flight mass spectrometry and automated data analysis. , 2005, Rapid communications in mass spectrometry : RCM.

[10]  T. Baillie,et al.  Metabolism and toxicity of drugs. Two decades of progress in industrial drug metabolism. , 2008, Chemical research in toxicology.

[11]  J. Castro-Pérez.  Current and future trends in the application of HPLC-MS to metabolite-identification studies. , 2007, Drug discovery today.

[12]  Mark Wrona,et al.  'All-in-one' analysis for metabolite identification using liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry with collision energy switching. , 2005, Rapid communications in mass spectrometry : RCM.