Directly-coupled HPLC-NMR spectroscopic studies of metabolism and futile deacetylation of phenacetin in the rat

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–C 2H 3 and urine samples were collected for −24–0 (pre-dosing), 0–8, 8–24, and 24–48 h post-dosing. Drug metaboli...

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Bibliographic Details
Published in:Journal of pharmaceutical and biomedical analysis 1999-09, Vol.20 (6), p.865-873
Main Authors: Nicholls, Andrew W, Lindon, John C, Farrant, R.Duncan, Shockcor, John P, Wilson, Ian D, Nicholson, Jeremy K
Format: Article
Language:English
Subjects:
2H labelling
4-Acetamidophenol
Acetaminophen - urine
Analgesics, Non-Narcotic - metabolism
Analgesics, Non-Narcotic - urine
Animals
Chromatography, High Pressure Liquid
Futile deacetylation
HPLC-NMR
Injections, Intraperitoneal
Magnetic Resonance Spectroscopy
Metabolites
Paracetamol
Phenacetin
Phenacetin - metabolism
Rat
Rats
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Summary: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–C 2H 3 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–C 2H 3. Quantitatively the percentage futile deacetylation of phenacetin–C 2H 3 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.
ISSN:0731-7085
1873-264X
DOI:10.1016/S0731-7085(99)00104-1