Skip to main content
SpringerLink
Log in

Relationship Between Structural Alerts in NSAIDs and Idiosyncratic Hepatotoxicity: An Analysis of Spontaneous Report Data from the WHO Database

  • Short Communication
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Background

Idiosyncratic drug reactions such as hepatotoxicity and blood dyscrasias represent one of the major causes of drug withdrawal from the market. According to the reactive metabolite (RM) concept, this may be due to the metabolic activation of structural alerts (SAs), functionalities in the drug molecule that are susceptible to bioactivation resulting in RMs. The relationship, however, between metabolic activation of SAs in drugs with in vivo toxicity measured as disproportionate reporting of adverse drug reactions (ADRs) to the WHO VigiBase™ database has never been studied.

Objective

The objective of this study was to investigate whether reported associations of hepatotoxicity between NSAIDs with SAs and NSAIDs with mitigated SAs are disproportionately present in the ADR reporting VigiBase™ database of the WHO collaborating center (the Uppsala Monitoring Centre). The extent of disproportionality of these associations is compared with associations of NSAIDs and hemorrhage, an ADR not associated with the forming of RMs.

Methods

We calculated the reporting odds ratios for five NSAIDs [bromfenac (withdrawn), lumiracoxib (withdrawn), diclofenac, ibuprofen, and naproxen] associated with the MedDRA preferred terms: hepatic failure, hepatic function abnormal, hepatic necrosis, and hepatitis. The disproportionality of the association of these ADRs is compared with the preferred term hemorrhage.

Results

The results show that hepatotoxicity is more disproportionately reported in the WHO database for NSAIDs with SAs (bromfenac, lumiracoxib, diclofenac) than for NSAIDs where SAs are mitigated (ibuprofen and naproxen). This difference in reporting between NSAIDs with SAs and with mitigated SAs is not observed for the ADR hemorrhage, an ADR not associated with the forming of RMs.

Conclusions

This study shows that although spontaneous reports have many limitations, the findings are in line with previous research on the reactive metabolite concept. Whether SAs and the number of SAs in the NSAIDs actually play a role in the observed hepatotoxicity must be investigated in future studies.

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

Notes

  1. MedDRA® terminology is the international medical terminology developed under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). MedDRA® trademark is owned by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) on behalf of ICH.

References

  1. Kalgutkar AS, Gardner I, Obach RS, Shaffer CL, Callegari E, Henne KR, et al. A comprehensive listing of bioactivation pathways of organic functional groups. Curr Drug Metab. 2005;6(3):161–225.

    Article  CAS  PubMed  Google Scholar 

  2. Gunawan B, Kaplowitz N. Clinical perspectives on xenobiotic-induced hepatotoxicity. Drug Metab Rev. 2004;36(2):301–12.

    Article  CAS  PubMed  Google Scholar 

  3. Williams DP, Park BK. Idiosyncratic toxicity: the role of toxicophores and bioactivation. Drug Discov Today. 2003;8(22):1044–50.

    Article  CAS  PubMed  Google Scholar 

  4. Srivastava A, Maggs JL, Antoine DJ, Williams DP, Smith DA, Park BK. Role of reactive metabolites in drug-induced hepatotoxicity. Handb Exp Pharmacol. 2010;196:165–94.

    Article  CAS  PubMed  Google Scholar 

  5. Friedman MA, Woodcock J, Lumpkin MM, Shuren JE, Hass AE, Thompson LJ. The safety of newly approved medicines: do recent market removals mean there is a problem? JAMA. 1999;281(18):1728–34.

    Article  CAS  PubMed  Google Scholar 

  6. Banks AT, Zimmerman HJ, Ishak KG, Harter JG. Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the Food and Drug Administration as adverse reactions. Hepatology. 1995;22(3):820–7.

    Article  CAS  PubMed  Google Scholar 

  7. Pohl LR, Satoh H, Christ DD, Kenna JG. The immunologic and metabolic basis of drug hypersensitivities. Annu Rev Pharmacol Toxicol. 1988;28:367–87.

    Article  CAS  PubMed  Google Scholar 

  8. Regan SL, Maggs JL, Hammond TG, Lambert C, Williams DP, Park BK. Acyl glucuronides: the good, the bad and the ugly. Biopharm Drug Dispos. 2010;31(7):367–95.

    Article  CAS  PubMed  Google Scholar 

  9. Skonberg C, Olsen J, Madsen KG, Hansen SH, Grillo MP. Metabolic activation of carboxylic acids. Expert Opin Drug Metab Toxicol. 2008;4(4):425–38.

    Article  CAS  PubMed  Google Scholar 

  10. Mangold JB, Gu H, Rodriguez LC, Bonner J, Dickson J, Rordorf C. Pharmacokinetics and metabolism of lumiracoxib in healthy male subjects. Drug Metab Dispos. 2004;32(5):566–71.

    Article  CAS  PubMed  Google Scholar 

  11. Li Y, Slatter JG, Zhang Z, Li Y, Doss GA, Braun MP, Stearns RA, Dean DC, Baillie TA, Tang W. In vitro metabolic activation of lumiracoxib in rat and human liver preparations. Drug Metab Dispos. 2008;36(2):469–73.

    Article  CAS  PubMed  Google Scholar 

  12. Kang P, Dalvie D, Smith E, Renner M. Bioactivation of lumiracoxib by peroxidases and human liver microsomes: identification of multiple quinone imine intermediates and GSH adducts. Chem Res Toxicol. 2009;22(1):106–17.

    Article  CAS  PubMed  Google Scholar 

  13. Poon GK, Chen Q, Teffera Y, Ngui JS, Griffin PR, Braun MP, et al. Bioactivation of diclofenac via benzoquinone imine intermediates-identification of urinary mercapturic acid derivatives in rats and humans. Drug Metab Dispos. 2001;29(12):1608–13.

    CAS  PubMed  Google Scholar 

  14. Stepan AF, Walker DP, Bauman J, Price DA, Baillie TA, Kalgutkar AS, et al. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem Res Toxicol. 2011;24(9):1345–410.

    Article  CAS  PubMed  Google Scholar 

  15. The database of the World Health Organization Collaborating Centre for International Drug Monitoring (VigiBase) (version date: 3 Feb 2015). https://tools.who-umc.org/webroot/. Accessed 1 May 2014.

  16. Moore N, Hall G, Sturkenboom M, Mann R, Lagnaoui R, Begaud B. Biases affecting the proportional reporting ratio (PPR) in spontaneous reports pharmacovigilance databases: the example of sertindole. Pharmacoepidemiol Drug Saf. 2003;12(4):271–81.

    Article  PubMed  Google Scholar 

  17. Martin RM, Kapoor KV, Wilton LV, Mann RD. Underreporting of suspected adverse drug reactions to newly marketed (“black triangle”) drugs in general practice: observational study. BMJ. 1998;317(7151):119–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Alvarez-Requejo A, Carvajal A, Begaud B, Moride Y, Vega T, Arias LH. Under-reporting of adverse drug reactions. Estimate based on a spontaneous reporting scheme and a sentinel system. Eur J Clin Pharmacol. 1998;54(6):483–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Disclosures

The authors are indebted to the national pharmacovigilance centers that contributed data to the WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre (WHO-UMC), and therefore to this study. The opinions and conclusions, however, are not necessarily those of the various centers, nor of the WHO-UMC. The information originates from a variety of sources, and the likelihood that the suspected adverse reaction is drug related is not the same in all cases. For a statement regarding data released from the UMC, the WHO Collaborating Centre for International Drug Monitoring, please visit http://www.who-umc.org/graphics/25300.pdf.

Funding and conflict of interest

No sources of funding were used to assist in the preparation of this study. Naomi Jessurun and Eugène van Puijenbroek have no conflicts of interest that are directly relevant to the content of this study.

Author information

Authors and Affiliations

  1. Netherlands Pharmacovigilance Centre, ‘s-Hertogenbosch, Noord-Brabant, The Netherlands

    Naomi Jessurun & Eugene van Puijenbroek

  2. Department of Pharmacy, Pharmacotherapy and Pharmaceutical Care, University of Groningen, Groningen, The Netherlands

    Eugene van Puijenbroek

Authors
  1. Naomi Jessurun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eugene van Puijenbroek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naomi Jessurun.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jessurun, N., van Puijenbroek, E. Relationship Between Structural Alerts in NSAIDs and Idiosyncratic Hepatotoxicity: An Analysis of Spontaneous Report Data from the WHO Database. Drug Saf 38, 511–515 (2015). https://doi.org/10.1007/s40264-015-0282-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-015-0282-z

Keywords

Search

Navigation