Skip to main content
SpringerLink
Log in

The Effect of 4-Methylpyrazole on Oxidative Metabolism of Acetaminophen in Human Volunteers

  • Original Article
  • Published:
Journal of Medical Toxicology Aims and scope Submit manuscript

Abstract

Introduction

Acetaminophen (APAP) is commonly ingested in both accidental and suicidal overdose. Oxidative metabolism by cytochrome P450 2E1 (CYP2E1) produces the hepatotoxic metabolite, N-acetyl-p-benzoquinone imine. CYP2E1 inhibition using 4-methylpyrazole (4-MP) has been shown to prevent APAP-induced liver injury in mice and human hepatocytes. This study was conducted to assess the effect of 4-MP on APAP metabolism in humans.

Methods

This crossover trial examined the ability of 4-MP to inhibit CYP2E1 metabolism of APAP in five human volunteers. Participants received a single oral dose of APAP 80 mg/kg, both with and without intravenous 4-MP, after which urinary and plasma oxidative APAP metabolites were measured. The primary outcome was the fraction of ingested APAP excreted as total oxidative metabolites (APAP-CYS, APAP-NAC, APAP-GSH).

Results

Compared with APAP alone, co-treatment with 4-MP decreased the percentage of ingested APAP recovered as oxidative metabolites in 24-hour urine from 4.48 to 0.51% (95% CI = 2.31–5.63%, p = 0.003). Plasma concentrations of these oxidative metabolites also decreased.

Conclusions

These results show 4-MP effectively reduced oxidative metabolism of APAP in human volunteers ingesting a supratherapeutic APAP dose.

Trial Registration

ClinicalTrials.gov Identifier: NCT03878693

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest. 2012;122(4):1574–83. https://doi.org/10.1172/jci59755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Salmonson H, Sjoberg G, Brogren J. The standard treatment protocol for paracetamol poisoning may be inadequate following overdose with modified release formulation: a pharmacokinetic and clinical analysis of 53 cases. Clin Toxicol (Phila). 2018;56(1):63–8. https://doi.org/10.1080/15563650.2017.1339887.

    Article  CAS  Google Scholar 

  3. Marks DJB, Dargan PI, Archer JRH, Davies CL, Dines AM, Wood DM, et al. Outcomes from massive paracetamol overdose: a retrospective observational study. Br J Clin Pharmacol. 2017;83(6):1263–72. https://doi.org/10.1111/bcp.13214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cairney DG, Beckwith HK, Al-Hourani K, Eddleston M, Bateman DN, Dear JW. Plasma paracetamol concentration at hospital presentation has a dose-dependent relationship with liver injury despite prompt treatment with intravenous acetylcysteine. Clin Toxicol (Phila). 2016;54(5):405–10. https://doi.org/10.3109/15563650.2016.1159309.

    Article  CAS  Google Scholar 

  5. Abernethy DR, Greenblatt DJ, Divoll M, Ameer B, Shader RI. Differential effect of cimetidine on drug oxidation (antipyrine and diazepam) vs. conjugation (acetaminophen and lorazepam): prevention of acetaminophen toxicity by cimetidine. J Pharmacol Exp Ther. 1983;224(3):508–13.

    CAS  PubMed  Google Scholar 

  6. Mitchell MC, Schenker S, Speeg KV 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;73(2):383–91. https://doi.org/10.1172/JCI111223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rudd GD, Donn KH, Grisham JW. Prevention of acetaminophen-induced hepatic necrosis by cimetidine in mice. Res Commun Chem Pathol Pharmacol. 1981;32(2):369–72.

    CAS  PubMed  Google Scholar 

  8. Slattery JT, McRorie TI, Reynolds R, Kalhorn TF, Kharasch ED, Eddy AC. Lack of effect of cimetidine on acetaminophen disposition in humans. Clin Pharmacol Ther. 1989;46(5):591–7. https://doi.org/10.1038/clpt.1989.190.

    Article  CAS  PubMed  Google Scholar 

  9. Vendemiale G, Altomare E, Trizio T, Leandro G, Manghisi OG, Albano O. Effect of acute and chronic cimetidine administration on acetaminophen metabolism in humans. Am J Gastroenterol. 1987;82(10):1031–4.

    CAS  PubMed  Google Scholar 

  10. Critchley JAJH, Scott AW, Dyson EH, Jarvie DR, Prescott LF. Is there a place for cimetidine or ethanol in the treatment of paracetamol poisoning? Lancet. 1983;321(8338):1375–6. https://doi.org/10.1016/s0140-6736(83)92150-5.

    Article  Google Scholar 

  11. Miners JO, Attwood J, Birkett DJ. Determinants of acetaminophen metabolism: effect of inducers and inhibitors of drug metabolism on acetaminophen’s metabolic pathways. Clin Pharmacol Ther. 1984;35(4):480–6. https://doi.org/10.1038/clpt.1984.64.

    Article  CAS  PubMed  Google Scholar 

  12. Knodell RG, Browne DG, Gwozdz GP, Brian WR, Guengerich FP. Differential inhibition of individual human liver cytochromes P-450 by cimetidine. Gastroenterology. 1991;101(6):1680–91. https://doi.org/10.1016/0016-5085(91)90408-d.

    Article  CAS  PubMed  Google Scholar 

  13. Hazai E, Vereczkey L, Monostory K. Reduction of toxic metabolite formation of acetaminophen. Biochem Biophys Res Commun. 2002;291(4):1089–94. https://doi.org/10.1006/bbrc.2002.6541.

    Article  CAS  PubMed  Google Scholar 

  14. Akakpo JY, Ramachandran A, Kandel SE, Ni HM, Kumer SC, Rumack BH, et al. 4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes. Hum Exp Toxicol. 2018;37(12):1310–22. https://doi.org/10.1177/0960327118774902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yip L, Heard K. Potential adjunct treatment for high-risk acetaminophen overdose. Clin Toxicol (Phila). 2016;54(5):459. https://doi.org/10.3109/15563650.2016.1144889.

    Article  Google Scholar 

  16. Kiernan EA, Fritzges JA, Henry KA, Katz KD. A case report of massive acetaminophen poisoning treated with a novel “triple therapy”: N-acetylcysteine, 4-methylpyrazole, and hemodialysis. Case Rep Emerg Med. 2019;2019:1–4. https://doi.org/10.1155/2019/9301432.

    Article  Google Scholar 

  17. Jacobsen D, Sebastian CS, Barron SK, Carriere EW, McMartin KE. Effects of 4-methylpyrazole, methanol/ethylene glycol antidote, in healthy humans. J Emerg Med. 1990;8(4):455–61.

    Article  CAS  Google Scholar 

  18. Brent J, McMartin K, Phillips S, Aaron C, Kulig K. Methylpyrazole for toxic alcohols study G. fomepizole for the treatment of methanol poisoning. N Engl J Med. 2001;344(6):424–9. https://doi.org/10.1056/NEJM200102083440605.

    Article  CAS  PubMed  Google Scholar 

  19. Brent J, McMartin K, Phillips S, Burkhart KK, Donovan JW, Wells M, et al. Fomepizole for the treatment of ethylene glycol poisoning. N Engl J Med. 1999;340(11):832–8. https://doi.org/10.1056/Nejm199903183401102.

    Article  CAS  PubMed  Google Scholar 

  20. Gade C, Dalhoff K, Petersen TS, Riis T, Schmeltz C, Chabanova E, et al. Higher chlorzoxazone clearance in obese children compared with nonobese peers. Br J Clin Pharmacol. 2018;84(8):1738–47. https://doi.org/10.1111/bcp.13602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. van Rongen A, Valitalo PAJ, Peeters MYM, Boerma D, Huisman FW, van Ramshorst B, et al. Morbidly obese patients exhibit increased CYP2E1-mediated oxidation of acetaminophen. Clin Pharmacokinet. 2016;55(7):833–47. https://doi.org/10.1007/s40262-015-0357-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Michaut A, Moreau C, Robin MA, Fromenty B. Acetaminophen-induced liver injury in obesity and nonalcoholic fatty liver disease. Liver Int. 2014;34(7):e171–9. https://doi.org/10.1111/liv.12514.

    Article  CAS  PubMed  Google Scholar 

  23. Nguyen GC, Sam J, Thuluvath PJ. Hepatitis C is a predictor of acute liver injury among hospitalizations for acetaminophen overdose in the United States: a nationwide analysis. Hepatology (Baltimore, Md). 2008;48(4):1336–41. https://doi.org/10.1002/hep.22536.

    Article  CAS  Google Scholar 

  24. Vance MV, Selden BS, Clark RF. Optimal patient position for transport and initial management of toxic ingestions. Ann Emerg Med. 1992;21(3):243–6.

    Article  CAS  Google Scholar 

  25. Chiew A, Day P, Salonikas C, Naidoo D, Graudins A, Thomas R. The comparative pharmacokinetics of modified-release and immediate-release paracetamol in a simulated overdose model. Emerg Med Australas. 2010;22(6):548–55. https://doi.org/10.1111/j.1742-6723.2010.01354.x.

    Article  PubMed  Google Scholar 

  26. Xie Y, McGill MR, Cook SF, Sharpe MR, Winefield RD, Wilkins DG, et al. Time course of acetaminophen-protein adducts and acetaminophen metabolites in circulation of overdose patients and in HepaRG cells. Xenobiotica. 2015;45(10):921–9. https://doi.org/10.3109/00498254.2015.1026426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. de Winter JCF. Using the Student’s t-test with extremely small sample sizes. Pract Assess Res Eval. 2013;18(10).

  28. Gelotte CK, Auiler JF, Lynch JM, Temple AR, Slattery JT. Disposition of acetaminophen at 4, 6, and 8 g/day for 3days in healthy young adults. Clin Pharmacol Ther. 2007;81(6):840–8. https://doi.org/10.1038/sj.clpt.6100121.

    Article  CAS  PubMed  Google Scholar 

  29. James LP, Chiew A, Abdel-Rahman SM, Letzig L, Graudins A, Day P, et al. Acetaminophen protein adduct formation following low-dose acetaminophen exposure: comparison of immediate-release vs extended-release formulations. Eur J Clin Pharmacol. 2013;69(4):851–7. https://doi.org/10.1007/s00228-012-1410-7.

    Article  PubMed  Google Scholar 

  30. Manyike PT, Kharasch ED, Kalhorn TF, Slattery JT. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther. 2000;67(3):275–82. https://doi.org/10.1067/mcp.2000.104736.

    Article  CAS  PubMed  Google Scholar 

  31. Akakpo JY, Ramachandran A, Duan L, Schaich MA, Jaeschke MW, Freudenthal BD, et al. Delayed treatment with 4-methylpyrazole protects against acetaminophen hepatotoxicity in mice by inhibition of c-Jun N-terminal kinase. Toxicol Sci. 2019;170(1):57–68. https://doi.org/10.1093/toxsci/kfz077.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

JYA and HJ were financially supported by NIH grants R01 DK102142 and P30 GM118247.

Author information

Authors and Affiliations

  1. Division of Clinical Data Analytics and Decision Support, and Division of Medical Toxicology and Precision Medicine, Department of Medicine, University of Arizona College of Medicine – Phoenix, Phoenix, AZ, USA

    A. Min Kang & Steven C. Curry

  2. Department of Medical Toxicology, Banner – University Medical Center Phoenix, 1012 E. Willetta St., Fl 2, Phoenix, AZ, 85006, USA

    A. Min Kang, Angela Padilla-Jones, Erik S. Fisher, Richard D. Gerkin & Steven C. Curry

  3. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA

    Jephte Y. Akakpo & Hartmut Jaeschke

  4. Department of Emergency Medicine, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA

    Barry H. Rumack

Authors
  1. A. Min Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Angela Padilla-Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erik S. Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jephte Y. Akakpo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hartmut Jaeschke
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Barry H. Rumack
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Richard D. Gerkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Steven C. Curry
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Min Kang.

Ethics declarations

Each participant provided informed consent and was randomized by blind draw from an envelope to start with one of two treatments (A or B), followed by crossover to the other treatment. This study was approved by the University of Arizona Institutional Review Board and registered with ClinicalTrials.gov (NCT03878693).

Conflicts of Interest

None.

Additional information

Supervising Editor: Eric Lavonas, MD

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kang, A.M., Padilla-Jones, A., Fisher, E.S. et al. The Effect of 4-Methylpyrazole on Oxidative Metabolism of Acetaminophen in Human Volunteers. J. Med. Toxicol. 16, 169–176 (2020). https://doi.org/10.1007/s13181-019-00740-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13181-019-00740-z

Keywords

Search

Navigation