title: Directly-coupled HPLC-NMR spectroscopic studies of metabolism and futile deacetylation of phenacetin in the rat.
abstract: The metabolism and futile deacetylation of phenacetin has been investigated in the rat via 1H NMR spectroscopic analysis of urine. Animals were dosed with either phenacetin or phenacetin-C2H3 and urine samples were collected for -24-0 (pre-dosing), 0-8. 8-24, and 24-48 h post-dosing. Drug metabolites of the two compounds were concentrated from the urine using solid-phase extraction prior to the use of directly-coupled HPLC-1H NMR spectroscopy for separation and identification. Following dosing of phenacetin, the metabolites identified were paracetamol glucuronide, paracetamol and N-hydroxyparacetamol, whilst paracetamol and N-hydroxyparacetamol sulphate were identified following dosing of phenacetin-C2H3. Quantitatively the percentage futile deacetylation of phenacetin-C2H3 metabolites was found to be 32% in both paracetamol and N-hydroxyparacetamol sulphate. This study further indicated the importance of futile deacetylation in simple analgesics and the value of directly-coupled HPLC-NMR spectroscopy for the study of this process.
authors.affiliation: Section of Biological Chemistry, Imperial College of Science, Technology and Medicine, London, UK. a.nicholls@ic.ac.uk
authors.forename: A W
authors.initials: AW
authors.lastname: Nicholls
authors.forename: J C
authors.initials: JC
authors.lastname: Lindon
authors.forename: R D
authors.initials: RD
authors.lastname: Farrant
authors.forename: J P
authors.initials: JP
authors.lastname: Shockcor
authors.forename: I D
authors.initials: ID
authors.lastname: Wilson
authors.forename: J K
authors.initials: JK
authors.lastname: Nicholson
mesh_terms: D000082:Acetaminophen / Q000652:urine; D018712:Analgesics, Non-Narcotic / Q000378:metabolism* / Q000652:urine; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D007274:Injections, Intraperitoneal; D009682:Magnetic Resonance Spectroscopy; D010615:Phenacetin / Q000378:metabolism*; D051381:Rats
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D010615:Phenacetin