University of Tasmania
whole_D'SouzaConradAgnello1984_thesis.pdf (3.81 MB)

Metabolism of phenacetin in the rat

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posted on 2023-05-27, 00:12 authored by D'Souza, Conrad Agnello
The abuse of phenacetin-containing analgesic mixtures has been linked epidemiologically with nephrotoxicity and carcinogenicity in man. In addition, clinical and histopathological tests after chronic administration of phenacetin in man and animals have indicated that it is nephrotoxic and carcinogenic. Furthermore, it has a chemical similarity to other known carcinogenic arylamides. However, the induction of toxicity with phenacetin remains a controversial subject. A number of chronic dosing studies with phenacetin have been carried out to demonstrate the ability of the drug to induce carcinogenesis and nephropathy. However, none have sought to explain the reasons for the chronic nature of phenacetin toxicity on the basis of the increased formation of toxic metabolites after continued administration of the drug. In the present chronic daily-dosing study with phenacetin in the rat, the metabolism of the drug was monitored by analysing urine samples at regular weekly intervals. Particular attention was paid to the formation of N-hydroxyphenacetin, which has been implicated in phenacetin carcinogenicity. The metabolism of phenacetin was monitored in five groups of Hooded Wistar rats. Each group was subjected to a different treatment. The purpose was to elucidate the effects of the size of the dose, duration of treatment, influence of commonly co-administered drugs (aspirin, caffeine) and the influence of a sulfation inhibitor (pentachlorophenol) on the metabolism of phenace tin. The metabolic trends indicated auto-induction of Nhydroxylation, evidenced by the increased formation of Nhydroxyphenacetin in all treatments. The induction was most pronounced with the large dose of phenacetin and, significantly, was prominent with the co-administration of aspirin at the lower dose of phenacetin. Paracetamol-sulfate was the major metabolite of phenacetin in the rat, while paracetamol-glucuronide and free paracetamol were the other products of the deethylation pathway of phenacetin. The mercapturate and cysteinyl conjugates were not detected. Pentachlorophenol, a known inhibitor of sulfation, did not block sulfation completely. The partial suppression of sulfation with pentachlorophenol resulted in the increased formation of 2- hydroxy-p-phenetidine and yielded a larger fraction of unchanged phenacetin in the urine. The metabolism of p-phenetidine, a deacetylated metabolite of phenacetin, was followed in freshly isolated rat hepatocytes. The biotransformation of p-phenetidine to phenacetin and 2- hydroxyphenetidine indicated that N-acetylation was significant in the Hooded Wistar rat. However, N-acetylation and aromatic hydroxylation did not fully account for the disappearance of p-phenetidine from the in vitro system.


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Copyright 1984 the Author - The University is continuing to endeavour to trace the copyright owner(s) and in the meantime this item has been reproduced here in good faith. We would be pleased to hear from the copyright owner(s). Thesis (M.Pharm.) - University of Tasmania, 1984. Bibliography: leaves 60-80

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