Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1973 Dec;49(4):602–613. doi: 10.1111/j.1476-5381.1973.tb08536.x

The effects of hepatic and renal damage on paracetamol metabolism and excretion following overdosage

A pharmacokinetic study

L F Prescott, N Wright
PMCID: PMC1776613  PMID: 4788034

Abstract

1. The kinetics of paracetamol metabolism and excretion were studied in 41 patients following overdosage. Acute hepatic necrosis developed in 23 patients and in 3 of these acute renal failure also occurred. Two patients died in hepatic failure.

2. Paracetamol metabolism was impaired in the patients with liver damage. The plasma half-life of the unchanged drug was significantly prolonged, and the ratio of the plasma concentrations of unchanged to conjugated paracetamol was significantly higher than in the patients without liver damage.

3. Paracetamol and its conjugates were rapidly excreted in the urine. However, excretion was slower in patients with liver damage and a higher proportion was excreted unchanged.

4. The renal clearance of unchanged (but not conjugated) paracetamol was related to the urine flow rate. However, forced diuresis is of no practical value and is contraindicated on clinical grounds. There was no correlation between urine pH and clearance of unchanged or conjugated drug.

5. In patients with hepatic necrosis there was a marked decrease in the overall elimination rate constant which could be accounted for by decreased metabolite formation. Except in patients with acute renal failure, the urinary excretion rate constants were similar to those observed in patients without liver damage.

Full text

PDF
602

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bloomer H. A., Maddock R. K., Jr, Sheehe J. B., Adams E. J. Rapid diagnosis of sedative intoxication by gas chromatography. Ann Intern Med. 1970 Feb;72(2):223–228. doi: 10.7326/0003-4819-72-2-223. [DOI] [PubMed] [Google Scholar]
  2. Clark R., Borirakchanyavat V., Davidson A. R., Thompson R. P., Widdop B., Goulding R., Williams R. Hepatic damage and death from overdose of paracetamol. Lancet. 1973 Jan 13;1(7794):66–70. doi: 10.1016/s0140-6736(73)90466-2. [DOI] [PubMed] [Google Scholar]
  3. Cummings A. J., King M. L., Martin B. K. A kinetic study of drug elimination: the excretion of paracetamol and its metabolites in man. Br J Pharmacol Chemother. 1967 Feb;29(2):150–157. doi: 10.1111/j.1476-5381.1967.tb01948.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cummings A. J., Martin B. K., Park G. S. Kinetic considerations relating to the accrual and elimination of drug metabolites. Br J Pharmacol Chemother. 1967 Feb;29(2):136–149. doi: 10.1111/j.1476-5381.1967.tb01947.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Jagenburg R., Nagy A., Rödjer S. Separation of p-acetamidophenol metabolites by gel filtration on Sephadex G 10. Scand J Clin Lab Invest. 1968;22(1):11–16. doi: 10.3109/00365516809160729. [DOI] [PubMed] [Google Scholar]
  6. Jollow D. J., Mitchell J. R., Potter W. Z., Davis D. C., Gillette J. R., Brodie B. B. Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther. 1973 Oct;187(1):195–202. [PubMed] [Google Scholar]
  7. Lawson A. A., Proudfoot A. T., Brown S. S., MacDonald R. H., Fraser A. G., Cameron J. C., Matthew H. Forced diuresis in the treatment of acute salicylate poisoning in adults. Q J Med. 1969 Jan;38(149):31–48. [PubMed] [Google Scholar]
  8. Levy G., Yamada H. Drug biotransformation interactions in man. 3. Acetaminophen and salicylamide. J Pharm Sci. 1971 Feb;60(2):215–221. doi: 10.1002/jps.2600600212. [DOI] [PubMed] [Google Scholar]
  9. Milne M. D. Influence of acid-base balance on efficacy and toxicity of drugs. Proc R Soc Med. 1965 Nov;58(11 Pt 2):961–963. doi: 10.1177/003591576505811P204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Mitchell J. R., Jollow D. J., Potter W. Z., Davis D. C., Gillette J. R., Brodie B. B. Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther. 1973 Oct;187(1):185–194. [PubMed] [Google Scholar]
  11. NELSON E., MORIOKA T. KINETICS OF THE METABOLISM OF ACETAMINOPHEN BY HUMANS. J Pharm Sci. 1963 Sep;52:864–868. doi: 10.1002/jps.2600520911. [DOI] [PubMed] [Google Scholar]
  12. Nusynowitz M. L., Forsham P. H. The antidiuretic action of acetaminophen. Am J Med Sci. 1966 Oct;252(4):429–435. doi: 10.1097/00000441-196610000-00008. [DOI] [PubMed] [Google Scholar]
  13. Prescott L. F. Gas-liquid chromatographic estimation of paracetamol. J Pharm Pharmacol. 1971 Oct;23(10):807–808. doi: 10.1111/j.2042-7158.1971.tb08613.x. [DOI] [PubMed] [Google Scholar]
  14. Prescott L. F., Roscoe P., Wright N., Brown S. S. Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet. 1971 Mar 13;1(7698):519–522. doi: 10.1016/s0140-6736(71)91125-1. [DOI] [PubMed] [Google Scholar]
  15. Prescott L. F. The gas-liquid chromatographic estimation of phenacetin and paracetamol in plasma and urine. J Pharm Pharmacol. 1971 Feb;23(2):111–115. doi: 10.1111/j.2042-7158.1971.tb08622.x. [DOI] [PubMed] [Google Scholar]
  16. Proudfoot A. T., Wright N. Acute paracetamol poisoning. Br Med J. 1970 Sep 5;3(5722):557–558. doi: 10.1136/bmj.3.5722.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Wrights N., Prescott L. F. Potentiation by previous drug therapy of hepatotoxicity following paracetamol overdosage. Scott Med J. 1973 Mar;18(2):56–58. doi: 10.1177/003693307301800205. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES