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Abstract

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.

Item Type:	Thesis - Coursework Master
Authors/Creators:	D'Souza, Conrad Agnello
Keywords:	Acetophenetidin
Copyright Holders:	The Author
Copyright Information:	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).
Additional Information:	Thesis (M.Pharm.) - University of Tasmania, 1984. Bibliography: leaves 60-80
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