NMR spectroscopic studies on the metabolism and futile deacetylation of phenacetin in the rat

• Published in: Xenobiotica Vol. 27; no. 11; pp. 1175 - 1186
• Main Authors: NICHOLLS, A. W., LINDON, J. C., CADDICK, S., FARRANT, R. D., WILSON, I. D., NICHOLSON, J. K.
• Format: Journal Article
• Language: English
• Published: London Informa UK Ltd 01.11.1997; Taylor & Francis
• Subjects: Acetaminophen - analogs & derivatives; Acetaminophen - urine; Acetylation; Animals; Biological and medical sciences; Deuterium; Drug toxicity and drugs side effects treatment; Magnetic Resonance Spectroscopy; Male; Medical sciences; Pharmacology. Drug treatments; Phenacetin - chemistry; Phenacetin - urine; Rats; Rats, Sprague-Dawley; Toxicity: urogenital system; Intraperitoneal administration; Urinary system disease; Rat; Rodentia; Metabolism toxicity relation; Kidney; Vertebrata; Paracetamol; Mammalia; Analgesic; Deacetylation; Animal; Phenacetin; Comparative study
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/004982597239930

1. 1H-NMR spectroscopy of urine was used to determine the % deacetylation and re-acetylation of 2H-labelled (in the acetyl) phenacetin metabolites in the rat. 2. Male Sprague- Dawley rats were each dosed with either phenacetin or phenacetin C2H8 at 50 mg kg−1. The total urinary recoveries for phenacetin and phenacetin-C2H8 were 47.6 ± 16.7 and 50.1 ± 16.2% respectively (not significantly different, p > 0.05). Paracetamol sulphate and glucuronide are the major urinary metabolites of both protio and deuteriophenace tin. 3. The futile deacetylationgiven by the urinary recovery of protio-acetyl metabolitesof phenacetin-C2H8 was 29.6 ± 0.9% for paracetamol sulphate and 36.6 ± 3.1% for paracetamol glucuronide. These observations demonstrate a high level of futile deacetylation in the paracetamol conjugates formed by metabolism of phenacetin-C2H8 and this may indicate a high metabolic flux through the nephrotoxic intermediate 4-aminophenol. 4. The level of futile deacetylation for phenacetin was significantly higher than that found previously in studies of labelled paracetamol in rat or man, and may be important in understanding the higher nephrotoxicity of phenacetin as compared with paracetamol.