title: Accelerated throughput metabolic route screening in early drug discovery using high-resolution liquid chromatography/quadrupole time-of-flight mass spectrometry and automated data analysis.
abstract: The resource investment required to characterise the metabolic fate of a compound is relatively large, meaning that within a drug discovery environment relatively few compounds are characterised in depth. Rate-limiting steps include the setting up of a complex array of mass spectrometry experiments and the subsequent analysis of the large data sets produced. We describe here a strategy for the evaluation of metabolic routes using full-scan high-resolution liquid chromatography/quadrupole time-of-flight mass spectrometry (LC/QToFMS) with automated data analysis using Metabolynx, a commercially available software package. Data from several structurally diverse compounds taken from the literature illustrate that, with careful setting of key parameters, this approach is able to indicate the presence of a wide range of metabolites with only a limited requirement for manual intervention.
authors.affiliation: The Neuroscience Research Centre, Merck Sharp and Dohme Ltd., Terlings Park, Harlow CM20 2QR, UK. russell_mortishire-smith@merck.com
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Mortishire-Smith
authors.forename: Desmond
authors.initials: D
authors.lastname: O'Connor
authors.forename: Jose M
authors.initials: JM
authors.lastname: Castro-Perez
authors.forename: Jane
authors.initials: J
authors.lastname: Kirby
mesh_terms: D000818:Animals; D001331:Automation; D002853:Chromatography, Liquid; D003975:Diazepam / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D019469:Indinavir / Q000737:chemistry / Q000378:metabolism; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D012015:Reference Standards; D012680:Sensitivity and Specificity; D013997:Time Factors
chemical_list: D004364:Pharmaceutical Preparations; D019469:Indinavir; D003975:Diazepam