title: Application of semi-automated metabolite identification software in the drug discovery process for rapid identification of metabolites and the cytochrome P450 enzymes responsible for their formation.
abstract: Rapid identification of metabolites of compound X using data dependent scan function of a quadrupole ion trap mass spectrometer and semi-automated metabolite identification software is described. Compound X is metabolized via monooxygenation and desmethylation. LC-ESI-MS spectra obtained, following incubations of Compound X with microsomes in the presence and absence of chemical inhibitors specific for CYP1A2, CYP3A4, CYP2D6, CYP2C9 and CYP2E1, were processed using semi-automated metabolite identification software to extract information and to identify the cytochrome P450 enzymes responsible for metabolite formation. Chemical inhibition data suggests that the primary cytochrome P450 (CYP450) isozyme responsible for the metabolism of compound X is CYP3A4 with a minor contribution from both CYP2D6 and CYP2E1. Additionally, neither CYP2C9 nor CYP1A2 appears to contribute to the metabolism of compound X.
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. ragu.ramanathan@pfizer.com
authors.forename: Ragu
authors.initials: R
authors.lastname: Ramanathan
authors.forename: Donald L
authors.initials: DL
authors.lastname: McKenzie
authors.forename: Meera
authors.initials: M
authors.lastname: Tugnait
authors.forename: Kristen
authors.initials: K
authors.lastname: Siebenaler
mesh_terms: D001331:Automation; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D013058:Mass Spectrometry; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D012984:Software; D013056:Spectrophotometry, Ultraviolet
chemical_list: D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System