title: Metabolism of 3-chloro-4-fluoroaniline in rat using [14C]-radiolabelling, 19F-NMR spectroscopy, HPLC-MS/MS, HPLC-ICPMS and HPLC-NMR.
abstract: The metabolic fate of 3-chloro-4-fluoroaniline was investigated in rat following intraperitoneal (i.p.) administration at 5 and 50 mg kg(-1) using a combination of HPLC-MS, HPLC-MS/MS, (19)F-NMR spectroscopy, HPLC-NMR spectroscopy and high-pressure liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICPMS) with (35)Cl and (34)S detection. The metabolism of 3-chloro-4-fluoroaniline at both doses was rapid and extensive, to a large number of metabolites, with little unchanged compound excreted via the urine. Dosing at 5 mg kg(-1) with [(14)C]-labelled compound enabled the comparison of standard radioassay analysis methods with (19)F-NMR spectroscopy. (19)F-NMR resonances were only readily detectable in the 0-12 h post-dose samples. Dosing at 50 mg kg(-1) allowed the facile and specific detection and quantification of metabolites by (19)F-NMR spectroscopy. Metabolite profiling was also possible at this dose level using HPLC-ICPMS with (35)Cl-specific detection. The principal metabolites of 3-chloro-4-fluoroaniline were identified as 2-amino-4-chloro-5-fluorophenyl sulfate and 2-acetamido-4-chloro-5-fluorophenyl glucuronide. N-acetylation and hydroxylation followed by O-sulfation were the major metabolic transformations observed.
authors.affiliation: Biological Chemistry, Division of Biomedical Sciences, Imperial College, London, UK. catherine_duckett@hotmail.com
authors.forename: C J
authors.initials: CJ
authors.lastname: Duckett
authors.forename: J C
authors.initials: JC
authors.lastname: Lindon
authors.forename: H
authors.initials: H
authors.lastname: Walker
authors.forename: F
authors.initials: F
authors.lastname: Abou-Shakra
authors.forename: I D
authors.initials: ID
authors.lastname: Wilson
authors.forename: J K
authors.initials: JK
authors.lastname: Nicholson
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000818:Animals; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes; D007553:Isotope Labeling / Q000379:methods; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000814:Aniline Compounds; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; C025654:3-chloro-4-fluoroaniline