Some new aspects of the metabolism of phenacetin in the rat

Nery, Rosane Maria

doi:10.1042/bj1220317

Cited by 46 publications

(10 citation statements)

References 17 publications

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“…Although phenacetin is metabolized predominantly to paracetamol, a proportion is converted by cytochrome P-450 to N-hydroxyphenacetin, which in turn is capable of forming both cytotoxic [13,14] and carcinogenic [15][16][17][18][19] derivatives. One of these, ^phenetidine, is cap able of being activated by prostaglandin hydroperoxi dase in the renal medulla [20].…”

Section: Discussionmentioning

confidence: 99%

Does Paracetamol Cause Urothelial Cancer or Renal Papillary Necrosis?

McCredie

Stewart

1988

Nephron

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The risk of developing renal papillary necrosis or cancer of the renal pelvis, ureter or bladder associated with consumption of either phenacetin or paracetamol was calculated from data acquired by questionnaire from 381 cases and 808 controls. The risk of renal papillary necrosis was increased nearly 20-fold by consumption of phenacetin, which also increased the risk for cancer of the renal pelvis and bladder but not for ureteric cancer. By contrast, we were unable to substantiate an increased risk from paracetamol consumption for renal papillary necrosis or any of these cancers although there was a suggestion of an association with cancer of the ureter.

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Section: Discussionmentioning

confidence: 99%

Does Paracetamol Cause Urothelial Cancer or Renal Papillary Necrosis?

McCredie

Stewart

1988

Nephron

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“…Like paracetamol, phenacetin is converted to a reactive alkylating metabolite which binds covalently to hepatic and renal tubular cell proteins causing necrosis (Mitchell et al, 1977). The reactive metabolite is probably a benzoquinone-imine derived from N-hydroxyphenacetin (Nery, 1971;Calder, Creek, Williams, Funder, Green, Ham & Tange, 1973).…”

Section: Kineticsmentioning

confidence: 99%

“…Phenacetin Phenacetin (acetophenetidine) is highly lipid-soluble with limited aqueous solubility, and its oral absorption is highly dependent on formulation factors such as particle size (Prescott, Steel & Ferrier, 1970 (Brodie & Axelrod, 1949;Jagenburg & Toczko, 1964;Buch, Pfleger, Rummel, Ullrich, Hey & Staudinger, 1967;Prescott, 1969;Raaflaub & Dubach, 1969;Nery, 1971;Uehleke, 1973;Smith & Timbrell, 1974;Klutch et al, 1978). There is extensive 'first-pass' metabolism of phenacetin by the small intestinal mucosa and liver, which is inducible by polycyclic hydrocarbons and cigarette smoking (Kuntzman, Pantuck, Kaplan & Conney, 1977).…”

Section: Kineticsmentioning

confidence: 99%

Kinetics and metabolism of paracetamol and phenacetin.

Prescott¹

1980

Brit J Clinical Pharma

396

279

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1 The rate of absorption of oral paracetamol depends on the rate of gastric emptying and is usually rapid and complete. The mean systemic availability is about 757o. 2 Paracetamol is extensively metabolized and the plasma half-life is 1.5-2.5 hours. About 55%o and 3007 of a therapeutic dose is excreted in the urine as glucuronide and sulphate conjugates, respectively, whereas mercapturic acid and cysteine conjugates (representing conversion to a potentially toxic intermediate metabolite) each account for some 4%o of the dose. Paracetamol metabolism is age-and dose-dependent. 3 With hepatotoxic doses, paracetamol metabolism is impaired and the half-life prolonged. Sulphate conjugation is saturated and the proportion excreted as mercapturic acid and cysteine conjugates is increased. 4 The renal clearance of paracetamol depends on urine flow rate by notpH. The renal clearances of' the glucuronide and sulphate conjugates often exceed the glomerular filtration rate and are independent of urine flow and pH. 5 Phenacetin absorption depends on formulation. It is extensively metabolized to paracetamol and minor metabolites are probably responsible for toxicity Paracetamol PARACETAMOL (acetaminophen, N-acetyl-p-aminophenol, 4-hydroxyacetanilide) is a moderately waterand lipid-soluble weak organic acid. It has a pKa value of 9.5 and is therefore largely unionized over the physiological range ofpH.

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“…NERY (1971) has suggested the N-hydroxylated derivative of phenacetin as an intermediate for such minor urinary metabolites as hydro quinone and acetamide. NERY (1971) has suggested the N-hydroxylated derivative of phenacetin as an intermediate for such minor urinary metabolites as hydro quinone and acetamide.…”

Section: Phenacetinmentioning

confidence: 99%

Concepts in Biochemical Pharmacology

Brodie¹,

Gillette²,

Ackerman³

1975

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This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machine or similar means, and storage in data banks. Under § 54 of the German Copyright Law where copies are made for other than private use, a fee is payable to the publlsher, the amount of the fee to be determined by agreement with the publisher. © by Springer-Verlag Berlin· Heidelberg 1975. Softcover reprint of the hardcover ist edition 1975 Library of Congress Cataloging in Publication Data (Revised) Main entry under title: Concepts in biochemical pharmacology. Handbuch der experlmentellen Pharmakologie. Handbook of experimental pharmacology. New series, v. XXVIII, 1, etc. Includes bibliographies. I. Drug metabolism-Collected works.!. Argy, W. P. II. Brodie, B. B., ed. III. Gillette, James R., 1928-ed. IV. Ackerman, Helen S., ed. V. Series: Handbuch der experimentellen Pharmakologle, v. XXVIII, 1 QP905.H3 Bd. 28, t. 1, etc. [RM301] 615'. 7 79-135957 ISBN 0-387-05134-1. The use of general descriptive names, trade names, trade marks, etc. in this pUblication, even if the former are not especially Identified, is not to be taken as a sign that such names, as understood by the Trade Marks and Merchandise Marks Act, may accordlngiy be used freely by anyone. PrefacePart 3 of the Handbook of Experimental Pharmacology (Concepts in Biochemical Pharmacology) applies the principles enunciated in Parts 1 and 2 to clinical pharmacology and toxicology. The major objective is to elucidate the many factors that determine the relationships between pharmacokinetic aspects of the disposition and metabolism of drugs and their therapeutic or toxic actions in man.Because of the more restricted information obtainable in human studies, this volume reflects the editors' bias that an understanding of pharmacokinetics is fundamental for assessing pharmacologic or toxicologic effects of drugs in humans. The first chapter is a unique primer on when to apply and how to use pharmacokinetic tools in human pharmacology. The second chapter explains the general assumptions underlying pharmacokinetic approaches both in simple terms for the novice and in mathematical form for the more sophisticated reader.Several chapters on determinants of drug concentration and activity discuss drug absorption, drug latentiation, drugs acting through metabolites, enterohepatic drug circulation, influence of route of drug administration on response, genetic variations in drug disposition and response, age differences in absorption, distribution and excretion of drugs, and pathologic and physiologic factors affecting absorption, distribution and excretion of drugs and drug response. The focus of these chapters is data obtained in human, rather than animal, studies. Most of the chapters contain new material never summarized previously.The section on drug interactions opens with a chapter in which all drug interactions are viewed as result...

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Some new aspects of the metabolism of phenacetin in the rat

Cited by 46 publications

References 17 publications

Does Paracetamol Cause Urothelial Cancer or Renal Papillary Necrosis?

Does Paracetamol Cause Urothelial Cancer or Renal Papillary Necrosis?

Kinetics and metabolism of paracetamol and phenacetin.

Concepts in Biochemical Pharmacology

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