Assessment of tramadol pharmacokinetics in correlation with CYP2D6 and clinical symptoms
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Mahnaz Ahmadimanesh
Abstract
Objectives
Due to lack of adequate data on tramadol kinetic in relevance of CYP2D6 toxicity, this study was designed to investigate the effect of CYP2D6 phenotype in tramadol poisoning. The saliva, urine and blood samples were taken at the admission time. Consequently, concentration of tramadol and its major metabolites were measured.
Methods
A pharmacokinetic and metabolic study was developed in cases of tramadol poisoned (n=96). Cases of tramadol poisoned evidenced seizure, hypertension, dizziness, nausea and vomiting symptoms participated.
Results
Female cases showed higher N-desmethyltramadol (M2) tramadol concentrations than male cases: in urine (40.12 ± 124.53 vs. 7.3 ± 7.13), saliva (16.91 ± 26.03 vs. 5.89 ± 7.02), and blood (1.11 ± 1.56 vs. 0.3 ± 0.38) samples. Significant correlation between blood, saliva, and urine concentrations were found (r = 0.5). Based on the metabolic ratio of O-desmethyltramadol (M1) of male (0.53 ± 0.22) and female (0.43 ± 0.26), poisoning and severe symptoms like seizure in female occurs statistically fewer (13.04%) than in male (50.6%). Assessment of CYP2D6 phenotype showed all of the participants were extensive metabolizers (EM) and their phenotype was associated with clinical symptoms.
Conclusions
According to our results, M1 as a high potent metabolite has an important role in toxicity and the likelihood of poisoning in people with EM phenotype. Finally, tramadol metabolic ratio may justify the cause of various symptoms in human tramadol poisoning.
Funding source: Tehran University of Medical Sciences and Health Services
Acknowledgments
Authors acknowledge the financial support provided by Tehran University of medical sciences, Tehran, Iran.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Research funding: Financial support was provided by the Tehran University of medical sciences, Tehran, Iran.
Competing interests: Authors state no conflict of interest.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: The study was approved by the Ethical review board of Tehran University of Medical Sciences.
References
1. Lassen, D, Damkier, P, Brøsen, K. The pharmacogenetics of tramadol. Clin Pharmacokinet 2015;54:825–36. https://doi.org/10.1007/s40262-015-0268-0.Suche in Google Scholar
2. Bamigbade, TA, Langford, RM. Tramadol hydrochloride: an overview of current use. J Hosp Med (London, England: 1998) 1998;59:373–6. 9722388.Suche in Google Scholar
3. Ardakani, YH, Rouini, MR. Improved liquid chromatographic method for the simultaneous determination of tramadol and its three main metabolites in human plasma, urine and saliva. J Pharmaceut Biomed Anal 2007;44:1168–73. https://doi.org/10.1016/j.jpba.2007.04.012.Suche in Google Scholar
4. Taghaddosinejad, F, Mehrpour, O, Afshari, R, Seghatoleslami, A, Abdollahi, M, Dart, RC. Factors related to seizure in tramadol poisoning and its blood concentration. J Med Toxicol 2011;7:183. https://doi.org/10.1007/s13181-011-0168-0.Suche in Google Scholar
5. Ahmed, AI, El-Dawy, K, Fawzy, MM, Abdallah, HA, Abd Elsaid, HN, Elmesslamy, WO. Retrospective review of tramadol abuse. J Vet Med Health Eco (VMHE) 2018;55, 16-19 October 2018. https://doi.org/10.26873/SVR-677-2018.Suche in Google Scholar
6. Massarella, J, Ariyawansa, J, Natarajan, J, Francke, S, Murtaugh, T, DeLemos, B, et al. Tramadol hydrochloride at steady state lacks clinically relevant QTc interval increases in healthy adults. Clin Pharm Drug Dev 2019;8:95–106. https://doi.org/10.1002/cpdd.473.Suche in Google Scholar
7. Giorgi, M, Del Carlo, S, Sgorbini, M, Saccomanni, G. Pharmacokinetics of tramadol and its metabolites M1, M2, and M5 in donkeys after intravenous and oral immediate release single-dose administration. J Equine Vet Sci 2009;29:569–74. https://doi.org/10.1016/j.jevs.2009.05.010.Suche in Google Scholar
8. Jimenez, TEP, Kukanich, B, Joo, H, Mealey, KL, Grubb, TL, Greene, SA. Oral coadministration of fluconazole with tramadol markedly increases plasma and urine concentrations of tramadol and the O-desmethyltramadol metabolite in healthy dogs. Drug Metab Dispos 2019;47:15–25. https://doi.org/10.1124/dmd.118.083444.Suche in Google Scholar
9. KuKanich, B, Papich, M. Pharmacokinetics of tramadol and the metabolite O‐desmethyltramadol in dogs. J Vet Pharmacol Therapeut 2004;27:239–46. https://doi.org/10.1111/j.1365-2885.2004.00578.x.Suche in Google Scholar
10. Lai, J, Ma, SW, Porreca, F, Raffa, RB. Tramadol, M1 metabolite and enantiomer affinities for cloned human opioid receptors expressed in transfected HN9. 10 neuroblastoma cells. Eur J Pharmacol 1996;316:369–72.10.1016/S0014-2999(96)00770-4Suche in Google Scholar
11. Gillen, C, Haurand, M, Kobelt, DJ, Wnendt, S. Affinity, potency and efficacy of tramadol and its metabolites at the cloned human µ-opioid receptor. Naunyn-Schmiedeberg’s Arch Pharmacol 2000;362:116–21. https://doi.org/10.1007/s002100000266.Suche in Google Scholar PubMed
12. Perez, TE, Mealey, KL, Grubb, TL, Greene, SA. Tramadol metabolism to O-desmethyl tramadol (M1) and N-desmethyl tramadol (M2) by dog liver microsomes: species comparison and identification of responsible canine cytochrome P450s. Drug Metab Dispos 2016;44:1963–72. https://doi.org/10.1124/dmd.116.071902.Suche in Google Scholar PubMed PubMed Central
13. Sheweita, SA, Almasmari, AA, El-Banna, SG. Tramadol-induced hepato-and nephrotoxicity in rats: role of Curcumin and Gallic acid as antioxidants. PloS One 2018;13:e0202110. https://doi.org/10.1371/journal.pone.0202110.Suche in Google Scholar PubMed PubMed Central
14. García-Quetglas, E, Azanza, JR, Sádaba, B, Muñoz, MJ, Gil, I, Campanero, MA. Pharmacokinetics of tramadol enantiomers and their respective phase I metabolites in relation to CYP2D6 phenotype. Pharmacol Res 2007;55:122–30. https://doi.org/10.1016/j.phrs.2006.11.003.Suche in Google Scholar PubMed
15. Barbosa, J, Faria, J, Queirós, O, Moreira, R, Carvalho, F, Dinis-Oliveira, RJ. Comparative metabolism of tramadol and tapentadol: a toxicological perspective. Drug Metab Rev 2016;48:577–92. https://doi.org/10.1080/03602532.2016.1229788.Suche in Google Scholar PubMed
16. Zanger, UM, Schwab, M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Therapeut 2013;138:103–41. https://doi.org/10.1016/j.pharmthera.2012.12.007.Suche in Google Scholar PubMed
17. Miotto, K, Cho, AK, Khalil, MA, Blanco, K, Sasaki, JD, Rawson, R. Trends in tramadol: pharmacology, metabolism, and misuse. Anesth Analg 2017;124:44–51. https://doi.org/10.1213/ANE.0000000000001683.Suche in Google Scholar PubMed
18. World Health Organization. Tramadol update review report agenda item 6.1;2014. Available from: https://www.who.int/medicines/areas/quality_safety/6_1_Update.pdf [cited 2019].Suche in Google Scholar
19. Ahmadimanesh, M, Shadnia, S, Rouini, MR, Sheikholeslami, B, Nasab, SA, Ghazi-Khansari, M. Correlation between plasma concentrations of tramadol and its metabolites and the incidence of seizure in tramadol-intoxicated patients. Drug Metab Pers Ther 2018;33:75–83. https://doi.org/10.1515/dmpt-2017-0040.Suche in Google Scholar PubMed
20. Stamer, U, Musshoff, F, Kobilay, M, Madea, B, Hoeft, A, Stuber, F. Concentrations of tramadol and O‐desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther 2007;82:41–7. https://doi.org/10.1038/sj.clpt.6100152.Suche in Google Scholar PubMed
21. Mehrpour, O, Sharifi, M, Zamani, N. Tramadol poisoning. In: Toxicology studies-cells, drugs and environment. London, UK: IntechOpen; 2015.10.5772/60439Suche in Google Scholar
22. Shadnia, S, Soltaninejad, K, Heydari, K, Sasanian, G, Abdollahi, M. Tramadol intoxication: a review of 114 cases. Hum Exp Toxicol 2008;27:201–5. https://doi.org/10.1177/0960327108090270.Suche in Google Scholar PubMed
23. Hariri, AT, Ahmadimanesh, M, Ghorbani, H, Seyedzade, E, Hejazi, A, Zarif, D, et al. Herbal medicines in Iran advertised as opioid withdrawal drugs-analysis by gas chromatography-mass spectrometry. Eur. J. Integr. Med 2019;25:55–9. https://doi.org/10.1016/j.eujim.2018.12.001.Suche in Google Scholar
24. Monte, AA, West, K, McDaniel, KT, Flaten, HK, Saben, J, Shelton, S, et al. CYP 2D6 genotype phenotype discordance due to drug‐drug interaction. Clin Pharmacol Ther 2018;104:933–9. https://doi.org/10.1002/cpt.1135.Suche in Google Scholar
25. Monte, AA,Heard, KJ, Campbell, J, Hamamura, D, Weinshilboum, RM, Vasiliou, V. The effect of CYP 2D6 drug–drug interactions on hydrocodone effectiveness. Acad Emerg Med 2014;21:879–85. https://doi.org/10.1111/acem.12431.Suche in Google Scholar
26. Wu, D, Otton, SV, Sproule, BA, Busto, U, Inaba, T, Kalow, W, et al. Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone. Br J Clin Pharmacol 1993;35:30–4. https://doi.org/10.1111/j.1365-2125.1993.tb05666.x.Suche in Google Scholar
27. Stamer, UM, Lehnen, K, Höthker, F, Bayerer, B, Wolf, S, Hoeft, A, et al. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain 2003;105:231–8. https://doi.org/10.1016/S0304-3959(03)00212-4.Suche in Google Scholar
28. Arafa, MH, Atteia, HH. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6) are associated with long term tramadol treatment-induced oxidative damage and hepatotoxicity. Toxicol Appl Pharmacol 2018;346:37–44. https://doi.org/10.1016/j.taap.2018.03.019.Suche in Google Scholar PubMed
29. Besic, N, Dolzan, V, Goricar, K, Jeriha, J, Strazisar, B. CYP2D6 phenotype and tramadol-related adverse events in breast cancer patients. Am Soc J Clin Oncol 2018;36(15 Suppl):e22186: https://doi.org/10.1200/jco.2018.36.15_suppl.e22186.Suche in Google Scholar
30. Rouini, M, Ardakani, Y. Pharmacokinetic study of tramadol and its three metabolites in plasma, saliva and urine. Daru 2009;17:245–55.Suche in Google Scholar
31. Ardakani, YH, Rouini, MR. Pharmacokinetics of tramadol and its three main metabolites in healthy male and female volunteers. Biopharm Drug Dispos 2007;28:527–34. https://doi.org/10.1002/bdd.584.Suche in Google Scholar PubMed
32. Ardakani, YH, Lavasani, H, Rouini, MR. Gender dependency in streoselective pharmacokinetics of tramadol and its phase I metabolites in relation to CYP2D6 phenotype in Iranian population. Iran J Pharm Res (IJPR): IJPR 2018;17:767. 29881433.Suche in Google Scholar
33. Ingelman-Sundberg, M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 2005;5:6. https://doi.org/10.1038/sj.tpj.6500285.Suche in Google Scholar PubMed
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Artikel in diesem Heft
- Original Articles
- Five genetic polymorphisms of cytochrome P450 enzymes in the Czech non-Roma and Czech Roma population samples
- Assessment of tramadol pharmacokinetics in correlation with CYP2D6 and clinical symptoms
- The particulars of certain drugs’ effect on the endogenous coenzyme Q10 plasma level in patients with cardiovascular diseases
- Evaluation of the suitability of 19 pharmacogenomics biomarkers for individualized metformin therapy for type 2 diabetes patients
- Self-estimation of phenylketonuria patients on therapeutic diet. Psychological support
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- Case Report
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Artikel in diesem Heft
- Original Articles
- Five genetic polymorphisms of cytochrome P450 enzymes in the Czech non-Roma and Czech Roma population samples
- Assessment of tramadol pharmacokinetics in correlation with CYP2D6 and clinical symptoms
- The particulars of certain drugs’ effect on the endogenous coenzyme Q10 plasma level in patients with cardiovascular diseases
- Evaluation of the suitability of 19 pharmacogenomics biomarkers for individualized metformin therapy for type 2 diabetes patients
- Self-estimation of phenylketonuria patients on therapeutic diet. Psychological support
- Double-blind trial of solid lipid Boswellia serrata particles (SLBSP) vs. standardized Boswellia serrata gum extract (BSE) for osteoarthritis of knee
- Case Report
- Meropenem for management of valproic acid overdose: a case report
