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General and renal toxicity of phenacetin, paracetamol and some anti-mitotic agents in the rat

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Abstract

The general and the renal toxicity of large doses of phenacetin, paracetamol, some antimitotic drugs and other constituents of analgesic mixtures was investigated in medium term toxicity tests in a large number of rats. Phenacetin and paracetamol depressed food intake and retarded growth. 800–1200 mg/kg · day paracetamol induced a larger mortality than 1500–3000 mg/kg · day phenacetin. Both analgesics and isophthalanilide, an antimitotic agent, induced hyperchromic anemia. Phenacetin induced methemoglobinemia more readily than paracetamol. Neither the analgesics, nor caffeine, sodium nitrite, isophthalanilide or mercaptopurine depressed GFR, maximal urinary concentration after dehydration plus vasopressin, urinary dilution after hypotonic expansion, or urinary acidification. Phenacetin, paracetamol and isophthalanilide depressed the fractional excretion of urea by the kidney. Very large doses of paracetamol slightly increased the proteinuria and the urinary excretion of tubular cells. Phenacetin and paracetamol induced degenerative histological alterations in cortical proximal and distal tubules, detected and quantitated under blind conditions. There were no inflammatory changes, nor any medullary or papillary lesions. The degenerative lesions could not be explained by the presence of methemoglobinemia or hemolysis. Isophthalanilide actually “improved” the histological appearance of the kidneys. The urinary excretion of tubular cells was not significantly correlated with the severity of the histological changes. It was concluded that neither phenacetin nor paracetamol exert major nephrotoxic effects in rats.

Zusammenfassung

Die allgemeine und renale Toxicität von großen Dosen von Phenacetin, Paracetamol und potentiell nephrotoxisehen Antimitotica, sowie anderen üblichen Bestandteilen von analgetischen Mischpräparaten wurde an Ratten in 30–60 Tage-Versuchen untersucht. Phenacetin und Paracetamol hemmten Futteraufnahme und Wachstum. 800–1200 mg/kg · Tag Paracetamol tötete mehr Tiere als 1500–3000 mg/kg · Tag Phenacetin. Die beiden Analgetica und das Antimitoticum Isophthalanilid riefen hyperchrome Anämie hervor. Phenacetin verursachte mehr Methämoglobinämie als Paracetamol. Weder dieser Analgetica, noch Coffein, noch Natriumnitrit, noch Isophthalanilid, noch Mercaptopurin verringerten das Glomerulusfiltrat, die maximale Harnkonzentrierungsfähigkeit nach Durst unter Vasopressin, die Harnverdünnuungsfähigkeit nach hypotonischen Infusionen oder die renale H+-Ionen-Sekretion. Phenacetin, Paracetamol und Isophthalanilid verringerten die fraktionelle renale Harnstoffausscheidung. Sehr große Dosen von Paracetamol steigerten leicht die Proteinurie und die Ausscheidung von Tubuluszellen im Harn. Phenacetin und Paracetamol verursachten degenerative Veränderungen im histologischen Bild der corticalen, proximalen und distalen Tubuli, die unter Blindbedingungen untersucht wurden. Es traten weder entzündliche Veränderungen, noch Schädigungen des Nierenmarks oder der Papille auf. Die corticalen degenerativen Veränderungen ließen sich nicht als Folge von Methämoglobinämie oder Hämolyse erklären. Isophthalanilid verursachte eine „Normalisierung” des histologischen Bilds der Nierenrinde über die Norm hinaus. Die Ausscheidung von Tubuluszellen im Harn war nicht signifikativ mit der Schwere der histologischen Veränderungen korreliert. Die Befunde führen zum Schluß, daß weder Phenacetin, noch Paracetamol bei der Ratte ausgeprägte nephrotoxische Wirkungen besitzt.

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Author notes

  1. Nicole Baechtold-Fowler

    Present address: Department of Physiology, Yale University, School of Medicine, New Haven, Conn., USA

  2. J. Ph. Bonjour

    Present address: Institut de physiopathologie de l'Université, Bern, Switzerland

  3. J. P. Guignard

    Present address: Departemento de nefrologia, Hospital de pediatria, C. H. N., Instituto mexicano del seguro social, Mexico 7, D.F.

  4. Chr. Hedinger & Erika Weber

    Present address: Pathologisches Institut der Universität Zürich, Switzerland

Authors and Affiliations

  1. Institut de Pharmacologie de l'Université and Institut de Pathologie de l'Université, Lausanne, Switzerland

    G. Peters, Nicole Baechtold-Fowler, J. Ph. Bonjour, Françoise Chométy-Diézi, Bernadette Filloux, R. Guidoux, J. P. Guignard, Lise Peters-Haefeli, Françoise Roch-Ramel, J. L. Schelling,  Chr. Hedinger & Erika Weber

  2. Institut für pathologische Anatomie der Universität, Schmelzbergstr. 12, CH-8006, Zürich, Switzerland

    Chr. Hedinger

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Supported by grants-in-aid of Office intercantonal pour le contrôle des médicaments, Bern, and Centre d'études sur les lymphômes malins, Lausanne as well as by research grants of Fonds National Suisse de la Recherche Scientifique.

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Peters, G., Baechtold-Fowler, N., Bonjour, J.P. et al. General and renal toxicity of phenacetin, paracetamol and some anti-mitotic agents in the rat. Arch. Toxikol. 28, 225–269 (1972). https://doi.org/10.1007/BF00330059

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