Skip to main content
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1991 Feb;31(2):139–142. doi: 10.1111/j.1365-2125.1991.tb05501.x

Inhibition of the metabolism of paracetamol by isoniazid.

M M Epstein 1, S D Nelson 1, J T Slattery 1, T F Kalhorn 1, R A Wall 1, J M Wright 1
PMCID: PMC1368379  PMID: 2049229

Abstract

1. The effect of isoniazid given daily for 7 days on paracetamol (acetaminophen) kinetics and metabolism was studied in 10 healthy volunteers. Paracetamol, 500 mg, was given before isoniazid, on day 7 of isoniazid administration, and 2 days after the last dose of isoniazid. 2. On day 7, isoniazid markedly inhibited the formation clearance of the glutathione and catechol metabolites by 69.7% and 62.2%, respectively. Total paracetamol clearance was lowered by 15.2%. There was no effect of isoniazid on the non-oxidative pathways of paracetamol elimination. 3. Two days after isoniazid was discontinued, paracetamol metabolism had returned to pre-isoniazid values.

Full text

PDF
139

Selected References

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

  1. Albano E., Rundgren M., Harvison P. J., Nelson S. D., Moldéus P. Mechanisms of N-acetyl-p-benzoquinone imine cytotoxicity. Mol Pharmacol. 1985 Sep;28(3):306–311. [PubMed] [Google Scholar]
  2. Andrews R. S., Bond C. C., Burnett J., Saunders A., Watson K. Isolation and identification of paracetamol metabolites. J Int Med Res. 1976;4(4 Suppl):34–39. doi: 10.1177/14732300760040S408. [DOI] [PubMed] [Google Scholar]
  3. Black M. Acetaminophen hepatotoxicity. Annu Rev Med. 1984;35:577–593. doi: 10.1146/annurev.me.35.020184.003045. [DOI] [PubMed] [Google Scholar]
  4. Critchley J. A., Dyson E. H., Scott A. W., Jarvie D. R., Prescott L. F. Is there a place for cimetidine or ethanol in the treatment of paracetamol poisoning? Lancet. 1983 Jun 18;1(8338):1375–1376. doi: 10.1016/s0140-6736(83)92150-5. [DOI] [PubMed] [Google Scholar]
  5. Dahlin D. C., Miwa G. T., Lu A. Y., Nelson S. D. N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci U S A. 1984 Mar;81(5):1327–1331. doi: 10.1073/pnas.81.5.1327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Davis M., Simmons C. J., Harrison N. G., Williams R. Paracetamol overdose in man: relationship between pattern of urinary metabolites and severity of liver damage. Q J Med. 1976 Apr;45(178):181–191. [PubMed] [Google Scholar]
  7. Kutt H., Brennan R., Dehejia H., Verebely K. Diphenylhydantoin intoxication. A complication of isoniazid therapy. Am Rev Respir Dis. 1970 Mar;101(3):377–384. doi: 10.1164/arrd.1970.101.3.377. [DOI] [PubMed] [Google Scholar]
  8. Mitchell J. R., Jollows D. J. Progress in hepatology. Metabolic activation of drugs to toxic substances. Gastroenterology. 1975 Feb;68(2):392–410. [PubMed] [Google Scholar]
  9. Mitchell J. R., Thorgeirsson S. S., Potter W. Z., Jollow D. J., Keiser H. Acetaminophen-induced hepatic injury: protective role of glutathione in man and rationale for therapy. Clin Pharmacol Ther. 1974 Oct;16(4):676–684. doi: 10.1002/cpt1974164676. [DOI] [PubMed] [Google Scholar]
  10. Mitchell J. R., Zimmerman H. J., Ishak K. G., Thorgeirsson U. P., Timbrell J. A., Snodgrass W. R., Nelson S. D. Isoniazid liver injury: clinical spectrum, pathology, and probable pathogenesis. Ann Intern Med. 1976 Feb;84(2):181–192. doi: 10.7326/0003-4819-84-2-181. [DOI] [PubMed] [Google Scholar]
  11. Mitchell M. C., Schenker S., Speeg K. V., Jr Selective inhibition of acetaminophen oxidation and toxicity by cimetidine and other histamine H2-receptor antagonists in vivo and in vitro in the rat and in man. J Clin Invest. 1984 Feb;73(2):383–391. doi: 10.1172/JCI111223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Morgan E. T., Koop D. R., Coon M. J. Comparison of six rabbit liver cytochrome P-450 isozymes in formation of a reactive metabolite of acetaminophen. Biochem Biophys Res Commun. 1983 Apr 15;112(1):8–13. doi: 10.1016/0006-291x(83)91789-8. [DOI] [PubMed] [Google Scholar]
  13. Muakkassah S. F., Bidlack W. R., Yang W. C. Mechanism of the inhibitory action of isoniazid on microsomal drug metabolism. Biochem Pharmacol. 1981 Jun 15;30(12):1651–1658. doi: 10.1016/0006-2952(81)90393-2. [DOI] [PubMed] [Google Scholar]
  14. Nouws J. F., Vree T. B., Breukink H. J., Baakman M., Driessens F., Smulders A. Dose dependent disposition of sulphadimidine and of its N4-acetyl and hydroxy metabolites in plasma and milk of dairy cows. Vet Q. 1985 Jul;7(3):177–186. doi: 10.1080/01652176.1985.9693980. [DOI] [PubMed] [Google Scholar]
  15. Ochs H. R., Greenblatt D. J., Verburg-Ochs B., Abernethy D. R., Knüchel M. Differential effects of isoniazid and oral contraceptive steroids on antipyrine oxidation and acetaminophen conjugation. Pharmacology. 1984;28(4):188–195. doi: 10.1159/000137961. [DOI] [PubMed] [Google Scholar]
  16. Prescott L. F. Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs. 1983 Mar;25(3):290–314. doi: 10.2165/00003495-198325030-00002. [DOI] [PubMed] [Google Scholar]
  17. Raucy J. L., Lasker J. M., Lieber C. S., Black M. Acetaminophen activation by human liver cytochromes P450IIE1 and P450IA2. Arch Biochem Biophys. 1989 Jun;271(2):270–283. doi: 10.1016/0003-9861(89)90278-6. [DOI] [PubMed] [Google Scholar]
  18. Ryan D. E., Koop D. R., Thomas P. E., Coon M. J., Levin W. Evidence that isoniazid and ethanol induce the same microsomal cytochrome P-450 in rat liver, an isozyme homologous to rabbit liver cytochrome P-450 isozyme 3a. Arch Biochem Biophys. 1986 May 1;246(2):633–644. doi: 10.1016/0003-9861(86)90319-x. [DOI] [PubMed] [Google Scholar]
  19. Slattery J. T., Levy G. Acetaminophen kinetics in acutely poisoned patients. Clin Pharmacol Ther. 1979 Feb;25(2):184–195. doi: 10.1002/cpt1979252184. [DOI] [PubMed] [Google Scholar]
  20. Slattery J. T., Wilson J. M., Kalhorn T. F., Nelson S. D. Dose-dependent pharmacokinetics of acetaminophen: evidence of glutathione depletion in humans. Clin Pharmacol Ther. 1987 Apr;41(4):413–418. doi: 10.1038/clpt.1987.50. [DOI] [PubMed] [Google Scholar]
  21. Timbrell J. A. The role of metabolism in the hepatotoxicity of isoniazid and iproniazid. Drug Metab Rev. 1979;10(1):125–147. doi: 10.3109/03602537908993904. [DOI] [PubMed] [Google Scholar]
  22. Wilson J. M., Slattery J. T., Forte A. J., Nelson S. D. Analysis of acetaminophen metabolites in urine by high-performance liquid chromatography with UV and amperometric detection. J Chromatogr. 1982 Feb 12;227(2):453–462. doi: 10.1016/s0378-4347(00)80398-9. [DOI] [PubMed] [Google Scholar]
  23. Wright J. M., Stokes E. F., Sweeney V. P. Isoniazid-induced carbamazepine toxicity and vice versa: a double drug interaction. N Engl J Med. 1982 Nov 18;307(21):1325–1327. doi: 10.1056/NEJM198211183072107. [DOI] [PubMed] [Google Scholar]

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

RESOURCES