title: Acute liver effects, disposition and metabolic fate of [14C]-fenclozic acid following oral administration to normal and bile-cannulated male C57BL/6J mice.
abstract: The distribution, metabolism, excretion and hepatic effects of the human hepatotoxin fenclozic acid were investigated following single oral doses of 10 mg/kg to normal and bile duct-cannulated male C57BL/6J mice. Whole body autoradiography showed distribution into all tissues except the brain, with radioactivity still detectable in blood, kidney and liver at 72 h post-dose. Mice dosed with [14C]-fenclozic acid showed acute centrilobular hepatocellular necrosis, but no other regions of the liver were affected. The majority of the [14C]-fenclozic acid-related material recovered was found in the urine/aqueous cage wash, (49%) whilst a smaller portion (13%) was eliminated via the faeces. Metabolic profiles for urine, bile and faecal extracts, obtained using liquid chromatography and a combination of mass spectrometric and radioactivity detection, revealed extensive metabolism of fenclozic acid in mice that involved biotransformations via both oxidation and conjugation. These profiling studies also revealed the presence of glutathione-derived metabolites providing evidence for the production of reactive species by mice administered fenclozic acid. Covalent binding to proteins from liver, kidney and plasma was also demonstrated, although this binding was relatively low (less than 50 pmol eq./mg protein).
authors.affiliation: Cyprotex Discovery Ltd, 15 Beech Lane, Macclesfield, Cheshire, SK10 2DR, UK.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Pickup
authors.affiliation: Drug Metabolism and Pharmacokinetics, Oncology iMED Chesterford Science Park, AstraZeneca UK Ltd., Saffron Walden, Essex, CB10 1XL, UK.
authors.forename: Scott
authors.initials: S
authors.lastname: Martin
authors.affiliation: Drug Metabolism and Pharmacokinetics IM, AstraZeneca UK Ltd, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Partridge
authors.affiliation: Global Safety Assessment Department, Alderley Park, AstraZeneca UK Ltd, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Huw B
authors.initials: HB
authors.lastname: Jones
authors.affiliation: Drug Metabolism and Pharmacokinetics IM, AstraZeneca UK Ltd, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wills
authors.affiliation: Sygnature Discovery, DMPK Department, BioCity, Nottingham, NG1 1GF, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Schulz-Utermoehl
authors.affiliation: In Vivo Assays Ltd, c/o Biohub, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: McCarthy
authors.affiliation: Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, Sherrington Building, University of Liverpool, Ashton Street, L69 3GE, Liverpool, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Rodrigues
authors.affiliation: Agilent Technologies Inc., 5500 Lakeside, Cheadle, SK8 3GR, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Page
authors.affiliation: Global Safety Assessment Department, Alderley Park, AstraZeneca UK Ltd, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Kerry
authors.initials: K
authors.lastname: Ratcliffe
authors.affiliation: Discovery Sciences IM, Milton Science Park, AstraZeneca UK Ltd., Cambridge, Cambridgeshire, CB40FZ, UK.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sarda
authors.affiliation: Department of Surgery and Cancer, Imperial College, Exhibition Rd, South Kensington, London, SW7 2AZ, UK. i.wilson@imperial.ac.uk.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Wilson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001646:Bile / Q000187:drug effects; D001652:Bile Ducts; D000072601:Cannula; D002250:Carbon Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005243:Feces; D008297:Male; D008810:Mice, Inbred C57BL; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D013844:Thiazoles; C100273:fenclozic acid
keywords: Fenclozic acid; Mouse; Reactive metabolites