title: 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.
abstract: 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.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, West Point, PA 19486, USA. philip_tiller@merck.com
authors.forename: Philip R
authors.initials: PR
authors.lastname: Tiller
authors.forename: Sean
authors.initials: S
authors.lastname: Yu
authors.forename: Jose
authors.initials: J
authors.lastname: Castro-Perez
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Fillgrove
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Baillie
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004285:Dogs; D020869:Gene Expression Profiling / Q000379:methods*; D005978:Glutathione / Q000493:pharmacokinetics*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods*
chemical_list: D005978:Glutathione