NMR SPECTROSCOPIC STUDIES ON THE METABOLISM AND FUTILE DEACETYLATION OF PHENACETIN IN THE RAT

1. H-1-NMR spectroscopy of urine was used to determine the 0/,, deacet ylation and re-acetylation of H-2-labelled (in the acetyl) phenacetin metabolites in the rat. 2. Male Sprague-Dawley rats were each dosed wi th either phenacetin or phenacetin-(CH3)-H-2 at 50 mg kg(-1). The tota l urinary recoveries for phenacetin and phenacetin-(CH3)-H-2 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 me tabolites of both protio and deuteriophenacetin. 3. The futile deacety lation given by the urinary recovery of protio-acetyl metabolites of p henacetin-(CH3)-H-2 was 29.6 +/- 0.9 % for paracetamol sulphate and 36 .6 +/- 3.1 % for paracetamol glucuronide. These observations demonstra te a high level of futile deacetylation in the paracetamol conjugates formed by metabolism of phenacerin-(CH3)-H-2 and this may indicate a h igh 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 nephro toxicity of phenacetin as compared with paracetamol.