title: The hepatic reductase null mouse as a model for exploring hepatic conjugation of xenobiotics: application to the metabolism of diclofenac.
abstract: The distribution, metabolism, excretion and hepatic effects of diclofenac were investigated following a single oral dose of 10 mg/kg to wild type and hepatic reductase null (HRN) mice.        For the HRN strain the bulk of the [(14)C]-diclofenac-related material was excreted in the urine/aqueous cagewash within 12 h of administration (~82%) with only small amounts eliminated via the faeces (~2% in 24 h). Wild type mice excreted the radiolabel more slowly with ca. 52 and 15% of the dose recovered excreted in urine and faeces, respectively, by 24 h post dose.        The metabolic profiles of the HRN mice were dominated by acyl conjugation to either taurine or glucuronic acid. Wild type mice produced relatively small amounts of the acyl glucuronide.        Whole Body Autoradiography (WBA) of mice sacrificed at 24 h post dose indicated increased retention of radioactivity in the livers of HRN mice compared to wild type mice. Covalent binding studies showed no differences between the two strains.        Metabolism of diclofenac in HRN mice involved mainly acyl glucuronide formation and taurine amide conjugation. This mouse model may find utility in understanding the impact of reactive metabolite formation via routes that involve the production of acyl-CoA or acyl glucuronides of acidic drugs.
authors.affiliation: Drug Metabolism and Pharmacokinetics IM, Alserley park, AstraZeneca UK Ltd., Macclesfield, Cheshire, United Kingdom. Kathryn.pickup@astrazeneca.com
authors.forename: Kathryn
authors.initials: K
authors.lastname: Pickup
authors.forename: Alex
authors.initials: A
authors.lastname: Gavin
authors.forename: Huw B
authors.initials: HB
authors.lastname: Jones
authors.forename: Elin
authors.initials: E
authors.lastname: Karlsson
authors.forename: Chris
authors.initials: C
authors.lastname: Page
authors.forename: Kerry
authors.initials: K
authors.lastname: Ratcliffe
authors.forename: Sunil
authors.initials: S
authors.lastname: Sarda
authors.forename: Timothy
authors.initials: T
authors.lastname: Schulz-Utermoehl
authors.forename: Ian
authors.initials: I
authors.lastname: Wilson
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004008:Diclofenac / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D008657:Metabolic Clearance Rate; D050217:Metabolic Detoxication, Phase II; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D015262:Xenobiotics / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D015262:Xenobiotics; D004008:Diclofenac; D009251:NADPH-Ferrihemoprotein Reductase