Skip to main content
SpringerLink
Log in

Metabolic ratios and SNPs implicated in tramadol-related deaths

  • Original Article
  • Published:
International Journal of Legal Medicine Aims and scope Submit manuscript

Abstract

Tramadol (TR) metabolism is performed by polymorphic enzymes that are influenced by genetic polymorphisms. Within this scope, the study presented here aimed to describe 41 genetic variants within CYP2D6, CYP2B6, and CYP3A4 genes in 48 cases of TR-related death that may be involved in the response to TR and to assess whether there is a correlation between these genetic variants and metabolic ratios (MRs). Blood samples from 48 victims of a TR-related death were analyzed to determine the concentrations of TR and its metabolites [O-desmethyltramadol (M1) & N-desmethyltramadol (M2)] using a LC–MS/MS method. All the samples were also genotyped for 41 common CYP2D6, CYP2B6, and CYP3A4 single nucleotide polymorphisms (SNPs) using the HaloPlex Target Enrichment system. Cases with the T/- genotype (rs35742686 in CYP2D6) had significantly higher M2/M1 ratio than cases with T/T genotype and cases with the G/A genotype (rs35599367 in CYP3A4) had significantly higher MR2 (TR/M2) ratio than cases with G/G genotype. The frequency of tested SNPs which belong to CYP2D6, CYP2B6, and CYP3A4 revealed the over-presentation of 2 SNPs (rs1058172 in CYP2D6 and rs4803419 in CYP2B6) in TR overdose group, which could have toxicological implications. These results indicate these polymorphisms in CYP2D6, CYP2B6, and CYP3A4 might influence the function and could increase the risk of toxicity. However, these findings should be supported in future studies with larger groups of cases.

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

Similar content being viewed by others

Data availability

The data presented in this study are available on request from the corresponding author.

References

  1. Aly SM, Gaulier J-M, Allorge D (2021) Pharmacogenetics and tramadol-related fatalities. In: Freckelton I (ed) Forensic Analysis - Scientific and Medical Techniques and Evidence under the Microscope. IntechOpen. https://doi.org/10.5772/intechopen.98250. Available at: https://www.intechopen.com/chapters/77331

  2. Aly SM, Omran A, Gaulier JM, Allorge D (2020) Substance abuse among children. Arch Pediatr 27: 480–4. S0929–693X(20)30205–0 [pii]. https://doi.org/10.1016/j.arcped.2020.09.006

  3. Hassamal S, Miotto K, Dale W, Danovitch I (2018) Tramadol: understanding the risk of serotonin syndrome and seizures. Am J Med 131: 1382 e1- e6. S0002–9343(18)30402–9 [pii]. https://doi.org/10.1016/j.amjmed.2018.04.025

  4. Dean L, Kane M (2021) Tramadol therapy and CYP2D6 genotype. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ (eds) Medical Genetics Summaries. National Center for Biotechnology Information (US). Available at: https://www.ncbi.nlm.nih.gov/books/NBK315950/

  5. Ahmad T, Sabet S, Primerano DA et al (2017) Tell-tale SNPs: the role of CYP2B6 in methadone fatalities. J Anal Toxicol 41: 325–33. 2981962 [pii] bkw135 [pii]. https://doi.org/10.1093/jat/bkw135

  6. Levo A, Koski A, Ojanperä I et al (2003) Post-mortem SNP analysis of CYP2D6 gene reveals correlation between genotype and opioid drug (tramadol) metabolite ratios in blood. Forensic Sci Int 135:9–15

    Article  CAS  PubMed  Google Scholar 

  7. Aly SM, Tartar O, Sabaouni N et al (2022) Tramadol-related deaths: genetic analysis in relation to metabolic ratios. J Anal Toxicol 46: 791–6. 6364335 [pii]. https://doi.org/10.1093/jat/bkab096

  8. Fonseca S, Amorim A, Costa HA et al (2016) Sequencing CYP2D6 for the detection of poor-metabolizers in post-mortem blood samples with tramadol. Forensic Sci Int 265: 153–9. S0379–0738(16)30017–2 [pii]. https://doi.org/10.1016/j.forsciint.2016.02.004

  9. Wendt FR, Novroski NM, Rahikainen A-L et al (2019) Supervised classification of CYP2D6 genotype and metabolizer phenotype with postmortem tramadol-exposed Finns. Am J Forensic Med Pathol 40:8–18

    Article  PubMed  Google Scholar 

  10. Schaffenburg W, Lockshin B, DeKlotz C (2021) Polymorphisms: why individual drug responses vary. In: Wolverton S, Wu J (eds) Comprehensive Dermatologic Drug Therapy, Elsevier, pp 21–33

  11. Haage P, Kronstrand R, Josefsson M et al (2018) Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype. Pharmacol Res Perspect 6:e00419

    Article  PubMed  PubMed Central  Google Scholar 

  12. Li B, Leal SM (2009) Deviations from Hardy-Weinberg equilibrium in parental and unaffected sibling genotype data. Hum Hered 67: 104–15. 000179558 [pii] hhe0067–0104 [pii]. https://doi.org/10.1159/000179558

  13. He X, He N, Ren L et al (2016) Genetic polymorphisms analysis of CYP2D6 in the Uygur population. BMC Genom 17:409. https://doi.org/10.1186/s12864-016-2719-x

    Article  CAS  Google Scholar 

  14. Ye Z, Wang Z, Hou Y (2020) Does Bonferroni correction “rescue” the deviation from Hardy-Weinberg equilibrium? Forensic Sci Int Genet 46:102254

    Article  CAS  PubMed  Google Scholar 

  15. Karlsson L, Green H, Zackrisson AL et al (2013) ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram. Int J Legal Med 127:579–586. https://doi.org/10.1007/s00414-013-0849-0

    Article  CAS  PubMed  Google Scholar 

  16. Roy Choudhury A, Cheng T, Phan L et al (2017) Supporting precision medicine by data mining across multi-disciplines: an integrative approach for generating comprehensive linkages between single nucleotide variants (SNVs) and drug-binding sites. Bioinformatics 33:1621–1629

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ji Y, Schaid DJ, Desta Z et al (2014) Citalopram and escitalopram plasma drug and metabolite concentrations: genome-wide associations. Br J Clin Pharmacol 78:373–383. https://doi.org/10.1111/bcp.12348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ahmed S, Khan H, Khan A et al (2021) Inter-ethnic genetic variations and novel variant identification in the partial sequences of CYP2B6 gene in Pakistani population. PeerJ 9: e11149. 11149 [pii]. https://doi.org/10.7717/peerj.11149

  19. Zubiaur P, Saiz-Rodriguez M, Ochoa D et al (2020) Influence of CYP2B6 activity score on the pharmacokinetics and safety of single dose efavirenz in healthy volunteers. Pharmacogenomics J 20:235–245. https://doi.org/10.1038/s41397-019-0103-3

    Article  CAS  PubMed  Google Scholar 

  20. El Akil S, Elouilamine E, Ighid N, Izaabel EH (2022) Explore the distribution of (rs35742686, rs3892097 and rs1065852) genetic polymorphisms of cytochrome P4502D6 gene in the Moroccan population. Egypt J Med Hum Genet 23:1–9

    Google Scholar 

  21. Wang D, Sadee W (2016) CYP3A4 intronic snp rs35599367 (CYP3A4* 22) alters RNA splicing. Pharmacogenet Genomics 26:40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Thanks to French Institute in Egypt for their support and help.

Author information

Authors and Affiliations

  1. Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

    Sanaa M. Aly

  2. CHU Lille, Service de Toxicologie-Génopathies, Lille, 59037, France

    Sanaa M. Aly, Florian Hakim, Camille Richeval, Benjamin Hennart, Jean-michel Gaulier & Delphine Allorge

  3. University of Lille, ULR 4483—IMPECS—IMPact de l’Environnement Chimique sur la Santé humaine, Lille, 59000, France

    Florian Hakim, Camille Richeval, Benjamin Hennart, Jean-michel Gaulier & Delphine Allorge

Authors
  1. Sanaa M. Aly
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Florian Hakim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Camille Richeval
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Benjamin Hennart
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean-michel Gaulier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Delphine Allorge
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sanaa M. Aly.

Ethics declarations

Ethical approval

The study approved by the CHU Lille, Unité Fonctionnelle de Toxicologie, research code: 131790 T (24 November 2022).

Consent to participate

It was waived due to the retrospective nature of the study.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aly, S.M., Hakim, F., Richeval, C. et al. Metabolic ratios and SNPs implicated in tramadol-related deaths. Int J Legal Med 137, 1431–1437 (2023). https://doi.org/10.1007/s00414-023-03052-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00414-023-03052-8

Keywords

Search

Navigation