title: Detection and characterization of metabolites in biological matrices using mass defect filtering of liquid chromatography/high resolution mass spectrometry data.
abstract: An improved mass defect filter (MDF) method employing both drug and core structure filter templates was applied to the processing of high resolution liquid chromatography/mass spectrometry (LC/MS) data for the detection and structural characterization of oxidative metabolites with mass defects similar to or significantly different from those of the parent drugs. The effectiveness of this approach was investigated using nefazodone as a model compound, which is known to undergo multiple common and uncommon oxidative reactions. Through the selective removal of all ions that fall outside of the preset filter windows, the MDF process facilitated the detection of all 14 nefazodone metabolites presented in human liver microsomes in the MDF-filtered chromatograms. The capability of the MDF approach to remove endogenous interferences from more complex biological matrices was examined by analyzing omeprazole metabolites in human plasma. The unprocessed mass chromatogram showed no distinct indication of metabolite peaks; however, after MDF processing, the metabolite peaks were easily identified in the chromatogram. Compared with precursor ion scan and neutral loss scan techniques, the MDF approach was shown to be more effective for the detection of metabolites in a complex matrix. The comprehensive metabolite detection capability of the MDF approach, together with accurate mass determination, makes high resolution LC/MS a useful tool for the screening and identification of both common and uncommon drug metabolites.
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA.
authors.forename: Mingshe
authors.initials: M
authors.lastname: Zhu
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Donglu
authors.initials: D
authors.lastname: Zhang
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ray
authors.forename: Weiping
authors.initials: W
authors.lastname: Zhao
authors.forename: W Griffith
authors.initials: WG
authors.lastname: Humphreys
authors.forename: Gary
authors.initials: G
authors.lastname: Skiles
authors.forename: Mark
authors.initials: M
authors.lastname: Sanders
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
mesh_terms: D001711:Biotransformation; D002853:Chromatography, Liquid / Q000379:methods*; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods*; D008956:Models, Chemical; D015394:Molecular Structure; D009853:Omeprazole / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D010879:Piperazines; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013678:Technology, Pharmaceutical / Q000379:methods; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D010879:Piperazines; D014230:Triazoles; C051752:nefazodone; D009853:Omeprazole