Skip to main content
Log in

The metabolism and toxicity of paracetamol in Sprague-Dawley and wistar rats

  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Summary

Urinary paracetamol metabolites from Sprague-Dawley and Wistar rats were analysed by reversed-phase HPLC. Variations in the metabolic profile were observed as a function of dose, age, sex, species and route of administration. In addition the effect of 3-methylcholanthrene as an inducer of cytochrome P450 mixed function oxidase on paracetamol metabolism was also studied. Increased oxidative metabolism which lead to the formation of 3-thiomethylparacetamol conjugates along with paracetamol mercapturic acid could be correlated with increased susceptibility to hepatic demage. Furthermore it appears that the length of time taken for excretion and the level of free drug excreted may be involved in the aetiology of chronic renal damage.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Proudfoot, A.T. and Wright, N. (1970). Acute Paracetamol Poisoning. Brit. Med. J.,3, 557–558.

    Article  CAS  PubMed  Google Scholar 

  2. Clark, R., Thompson, R.P.H., Borirakchanyavat, V., Widdop, B., Davidson, A.R., Goulding, R. and Williams, R. (1973). Hepatic damage and death from overdose of paracetamol. Lancet, 66–70.

  3. Edwards, O.M., Edwards, P., Huskisson, E.C. and Taylor, R.T. (1971). Paracetamol and renal damage. Brit. Med. J.,2, 87–89.

    Article  CAS  PubMed  Google Scholar 

  4. Boyer, T. and Rouff, S.L. Acetaminophen-Induced Hepatic Necrosis and Renal Failure. J.A.M.A.,218, 440–441.

  5. Wilkinson, S.P., Moodie, H., Arroyo, V.A. and Williams, R. (1977). Frequency of renal impairment in paracetamol overdose compared with other causes of acute liver damage. J. Clin. Path.,30, 141–143.

    Article  CAS  PubMed  Google Scholar 

  6. Duggin, G.G. (1980). Mechanisms in the development of analgesic nephropathy. Kidney International,13, 553–561.

    Article  Google Scholar 

  7. Jollow, D.J., Thorgeirsson, S.S., Potter, W.Z., Hashimoto, M. and Mitchell, J.R. (1974). Acetaminophen-Induced Hepatic Necrosis. VI Metabolic disposition of toxic and nontoxic doses of acetaminophen. Pharmacology,12, 251–271.

    Article  CAS  PubMed  Google Scholar 

  8. Davis, M., Harrison, N.G., Ideo, G., Portmann, Sb., Labadarios, D, and Williams, R. (1976). Paracetamol metabolism in the rat: Relationship to covalent binding and hepatic damage. Xenobiotica,6, 249–255.

    Article  CAS  PubMed  Google Scholar 

  9. Mitchell, J.R., Potter, W.Z., Hinson, J.A., Snodgrass, W.R., Timbrell, J.A. and Gillette, J.R. (1975). Toxic drug reactions in Handbood of Experimental Pharmacology. (Concepts in Biochem. Pharmacol.) Ed., Gillette, J.R. and Mitchell, J.R. Springer-Verlag, New York,28 (3), 383–417.

    Google Scholar 

  10. Hinson, J.A., Pohl, L.R. and Gillette, J.R. (1979). N-hydroxyacetaminophen: A microsomal metabolite of N-hydroxyphenacetin but apparently not of acetaminophen. Life Sei.,24, 2133–2138.

    Article  CAS  Google Scholar 

  11. Calder, I.C., Hart, S.J., Healey, K. and Ham, K.N. (1981). N-hydroxyacetaminophen: A postulated toxic intermediate of acetaminophen. J. Med. Chem.

  12. Crome, P., Volans, G.N., Vale, J.A., Widdop, B., Goulding, R. and Williams, R.S. (1976). The use of methionine for acute paracetamol poisoning. J. Int. Med. Res.,1, Supplement (4) 105–111

    Google Scholar 

  13. Prescott, L.R., Park, J. and Proudfoot, A.T. (1976). Cysteamine, L-methionine and D-penicillamine in paracetamol poisoning, J. Int. Med. Res.,4, Supplement (4) 112–117

    CAS  PubMed  Google Scholar 

  14. Mudge, G.H., Gemborys, M.W. and Duggin, G.G. (1978). Covalent binding of metabolites of acetaminophen to kidney protein and depletion of renal glutathione. J. Pharmacol. Exp. Ther.206, 218–226.

    CAS  PubMed  Google Scholar 

  15. McMurty, R.J., Snodgrass, W.R. and Mitchell, J.R. (1978). Renal necrosis, glutathione depletion and covalent binding after acetaminophen J. Toxicol. App. Pharmacol.46, 87–100.

    Article  Google Scholar 

  16. Andrews, R.S., Bond, C.C., Burnett, J., Saunders, A. and Watson, K. (1976). Isolation and identification of paracetamol metabolites. J. Int. Med. Res.,4, Supplement, (4) 34–39.

    CAS  PubMed  Google Scholar 

  17. Knox, J.H. and Jurand, J.J. (1977). Determination of paracetamol and its metabolites in urine by high performance liquid chromatography using reversedphase bonded supports. J. Chromatogr.,142, 651–670.

    Article  CAS  PubMed  Google Scholar 

  18. Mrochek, J.E., Katz, S., Chrishe, W.H. and Dinsmore, S.R. (1974). Acetaminophen metabolism in man, as determined by high resolution liquid chromatography. Clin. Chem.,20, 1086–1096.

    CAS  PubMed  Google Scholar 

  19. Smith, G.E. and Griffiths, L.A. (1976). Comparative metabolic studies of phenacetin and structurally-related compounds in the rat. Xenobiotica,6, 217–236.

    Article  CAS  PubMed  Google Scholar 

  20. Wong, L.T., Solomonraj, G. and Thomas, B.H. (1976). Metabolism of (14C)paracetamol and its interactions with aspirin in hamsters. Xenobiotica,6, 575–584.

    Article  CAS  PubMed  Google Scholar 

  21. Klutch, A., Levin, W., Chang, R.L., Vane, F. and Conney, A.H. (1978). Formation of a thiomethyl metabolite of phenacetin and acetaminophen in dogs and man. Clin. Pharmacol. Ther.,24, 287–293.

    CAS  PubMed  Google Scholar 

  22. Hart, S.J. Tontodonati, R. and Calder, I.C. (1981). Reverse phase chromatography of urinary metabolites of paracetamol using ion suppression and ion pairing. J. Chromatog.

  23. Andrews, R.S. (1980). Personal Communication.

  24. Calder, I.C, Yong, A.C., Woods, R.A., Crowe, C.A., Ham, K.N. and Tange, J.D. (1979). The nephrotoxicity of /7-aminophenol. II. The effect of metabolic inhibitors and inducers. Chem.-Biol. Interactions,27, 245–254.

    Article  CAS  Google Scholar 

  25. Healey, K., Calder, I.C, Yong, A.C., Crowe, CA., Funder, C.C., Ham. K.N. and Tange, J.D. (1978). Liver and kidney damage induced by N-hydroxy-paracetamol. Xenobiotica, 8, 403–411.

    Article  CAS  PubMed  Google Scholar 

  26. Calder, I.C, Hart, S.J., Emslie, K.R. and Tange, J.D. (1981). Metabolism of paracetamol by the isolated perfused kidney of the Homozygous Gunn Rat. Xenobiotica.

  27. Hart, S.J. and Calder, I.C. (unpublished work in this laboratory).

  28. Tateishi, M., Suzuki, S. and H. Shimizu (1979). The metabolism of bromazepam in the rat. Identification of mercapturic acid and its conversion in vitro to methylthio-bromazepam. Biochem. Pharmacol.27, 809–810.

    Article  Google Scholar 

  29. Calder, I.C, Funder, C.C., Green, CR., Ham, K.N. and Tange, J.D. (1971). Comparative nephrotoxicity of aspirin and phenacetin derivatives. Br. Med. J.4, 518–521.

    Article  CAS  PubMed  Google Scholar 

  30. Anders, M.W. (1980). Metabolism of drugs by the kidney. Kidney Int.18, 636–647.

    Article  CAS  PubMed  Google Scholar 

  31. Mitchell, J.R., McMurty, R.J., Statham, C.N. and Nelson, S.D. (1977). The molecular basis of several drug-induced nephropathies. Amer. J. Med.,62, 518–526.

    Article  CAS  PubMed  Google Scholar 

  32. Ross, B., Tange, J., Emslie, K., Hart, S., Smail, M. and Calder, I. (1980). Paracetamol metabolism by the isolated perfused rat kidney. Kidney Int.18, 562–570.

    Article  CAS  PubMed  Google Scholar 

  33. Hart, S., Calder, I., Ross, B. and Tange, J. (1980). Renal metabolism of paracetamol: studies in the isolated perfused rat kidney. Clin. Sei.58, 379–384.

    CAS  Google Scholar 

  34. Ham, K.N., Robinson, I.S., Calder, I.C, Mohandas, J. and Duggin, G.G. (1981). Chronic active hepatites following prolonged paracetamol (acetaminophen) ingestion, Med. J. Aust.,1, 538.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hart, S.J., Calder, I.C. & Tange, J.D. The metabolism and toxicity of paracetamol in Sprague-Dawley and wistar rats. European Journal of Drug Metabolism and Pharmacokinetics 7, 203–222 (1982). https://doi.org/10.1007/BF03189567

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03189567

Key words

Navigation