title: High temperature liquid chromatography hyphenated with ESI-MS and ICP-MS detection for the structural characterization and quantification of halogen containing drug metabolites.
abstract: In this paper we describe the hyphenation of high temperature liquid chromatography with ICP-MS and ESI-MS for the characterization of halogen containing drug metabolites. The use of temperature gradients up to 200°C enabled the separation of metabolites with low organic modifier content. This specific property allowed the use of detection methods that suffer from (significant) changes in analyte response factors as a function of the organic modifier content such as ICP-MS. Metabolites of two kinase inhibitors (SB-203580-Iodo and MAPK inhibitor VIII) produced by bacterial cytochrome P450 BM3 mutants and human liver microsomes were identified based on high resolution MS(n) data. Quantification was done using their normalized and elemental specific response in the ICP-MS. The importance of these kinds of quantification strategies is stressed by the observation that the difference of the position of one oxygen atom in a structure can greatly affect its response in ESI-MS and UV detection.
authors.affiliation: BioMolecular Analysis Group, Faculty of Sciences, VU University Amsterdam, The Netherlands.
authors.forename: Jon S B
authors.initials: JS
authors.lastname: de Vlieger
authors.forename: Mark J N
authors.initials: MJ
authors.lastname: Giezen
authors.forename: David
authors.initials: D
authors.lastname: Falck
authors.forename: Cornelis
authors.initials: C
authors.lastname: Tump
authors.forename: Fred
authors.initials: F
authors.lastname: van Heuveln
authors.forename: Martin
authors.initials: M
authors.lastname: Giera
authors.forename: Jeroen
authors.initials: J
authors.lastname: Kool
authors.forename: Henk
authors.initials: H
authors.lastname: Lingeman
authors.forename: Jaap
authors.initials: J
authors.lastname: Wieling
authors.forename: Maarten
authors.initials: M
authors.lastname: Honing
authors.forename: Hubertus
authors.initials: H
authors.lastname: Irth
authors.forename: Wilfried M A
authors.initials: WM
authors.lastname: Niessen
mesh_terms: D001966:Bromine / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D005260:Female; D006219:Halogens / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D007093:Imidazoles / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D007455:Iodine / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D057230:Limit of Detection; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D010100:Oxygen / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods
chemical_list: D006219:Halogens; D007093:Imidazoles; D004364:Pharmaceutical Preparations; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D007455:Iodine; C093642:SB 203580; D010100:Oxygen; D001966:Bromine