NMR spectroscopic studies on the metabolism and futile deacetylation of phenacetin in the rat.
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-C2H3 at 50 mg kg-1. The total urinary recoveries for phenacetin and phenacetin-C2H3 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 deuteriophenacetin. 3. The futile deacetylation given by the urinary recovery of protio-acetyl metabolites of phenacetin-C2H3 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-C2H3 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.
Nicholls
A W
AW
Department of Chemistry, Birkbeck College, London, UK.
Lindon
J C
JC
Caddick
S
S
Farrant
R D
RD
Wilson
I D
ID
Nicholson
J K
JK
D000082:Acetaminophen / Q000031:analogs & derivatives / Q000652:urine; D000107:Acetylation; D000818:Animals; D003903:Deuterium; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010615:Phenacetin / Q000737:chemistry / Q000652:urine*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000082:Acetaminophen; C037386:acetaminophen glucuronide; D003903:Deuterium; D010615:Phenacetin; C045667:acetaminophen sulfate ester