Abstract
Background:
Tramadol is prone to be abused alone, or in combination with 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). It was reported that 95% of people with a history of substance abuse in the United States used tramadol in 2004. According to the WHO report in 2016, there was a growing number of tramadol abusers alone or in combination with psychoactive substances such as MDMA in particular in some Middle East countries. Higher concentrations of tramadol in plasma may lead to adverse drug reactions or lethal intoxication. In this study, the effect of MDMA on the pharmacokinetics of tramadol was examined in male rats.
Methods:
The effect of MDMA on Tmax, Cmax, area under the curve, elimination rate, and half-life of tramadol and its metabolites was examined. Two control and two treatment groups were designed. The treatment groups received MDMA 18 h before the administration of tramadol. Jugular vein blood samples were analyzed by high-performance liquid chromatography with fluorescent detector to determine the concentrations of tramadol and its metabolites. Independent-sample t-test was used to define the differences between pharmacokinetic parameters of control and treatment groups.
Results:
When tramadol administered intraperitoneally, the absorption rate of this drug was reduced, and a lower Cmax (40%) with longer Tmax (eight-fold) was achieved. MDMA exerted greater inhibitory effects on cytochrome P450 3A4 (CYP3A4) than on cytochrome P450 2D6 (CYP2D6). The M2 metabolite ratio was reduced by half, and because of the inhibition of M2 production, the M1 plasma concentration slightly increased.
Conclusions:
According to the obtained data, MDMA treatment affected the absorption, distribution and metabolism phases of tramadol. This treatment increased the concentration of tramadol if administered intravenously and can latent the absorption of tramadol in oral route. However, MDMA was introduced as CYP2D6 inhibitor; in this study, MDMA inhibited CYP3A4 isoenzymes as well. This finding is important for the compounds that are metabolized through CYP3A4. It can be proposed that in abusers of MDMA who only receive tramadol for medical or nonmedical purposes in short intervals, the dangers of the intravenous administration of tramadol should be considered, and if tramadol is administered orally, the desired effect may not be achieved at the routine dose.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Overholser BR, Foster DR. Opioid pharmacokinetic drug-drug interactions. Am J Manag Care 2011;17(Suppl 11):S276–87.Search in Google Scholar PubMed
2. Epstein DH, Preston KL, Jasinski DR. Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: lessons from tramadol. Biol Psychol 2006;73:90–9.10.1016/j.biopsycho.2006.01.010Search in Google Scholar PubMed PubMed Central
3. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004;43:879–923.10.2165/00003088-200443130-00004Search in Google Scholar PubMed
4. Jesse CR, Wilhelm EA, Bortolatto CF, Nogueira CW. Evidence for the involvement of the noradrenergic system, dopaminergic and imidazoline receptors in the antidepressant-like effect of tramadol in mice. Pharmacol Biochem Behav 2010;95:344–50.10.1016/j.pbb.2010.02.011Search in Google Scholar PubMed
5. SAMHSA 2010. Cited 5/6/2012. Available at: http://www.samhsa.gov/data/NSDUH/2k10ResultsTables/Web/HTML/Sect1peTabs47to92.html.Search in Google Scholar
6. WHO. Thirty-sixth Meeting of Expert Committee on Drug Dependence Agenda Item 6.1 Tramadol Update Review Report. Geneva: 2014 16–20 June 2014.Search in Google Scholar
7. Leppert W. CYP2D6 in the metabolism of opioids for mild to moderate pain. Pharmacology 2011;87:274–85.10.1159/000326085Search in Google Scholar PubMed
8. Faron-Gorecka A, Kusmider M, Inan SY, Siwanowicz J, Piwowarczyk T, Dziedzicka-Wasylewska M. Long-term exposure of rats to tramadol alters brain dopamine and alpha 1-adrenoceptor function that may be related to antidepressant potency. Eur J Pharmacol 2004;501:103–10.10.1016/j.ejphar.2004.08.011Search in Google Scholar PubMed
9. Giorgi M, Saccomanni G, Lebkowska-Wieruszewska B, Kowalski C. Pharmacokinetic evaluation of tramadol and its major metabolites after single oral sustained tablet administration in the dog: a pilot study. Vet J 2009;180:253–5.10.1016/j.tvjl.2007.12.011Search in Google Scholar PubMed
10. 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 Pharm Biomed Anal 2007;44:1168–73.10.1016/j.jpba.2007.04.012Search in Google Scholar PubMed
11. Raffa RB. Basic pharmacology relevant to drug abuse assessment: tramadol as example. J Clin Pharm Ther 2008;33:101–8.10.1111/j.1365-2710.2008.00897.xSearch in Google Scholar PubMed
12. Gillen C, Haurand M, Kobelt DJ, Wnendt S. Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn Schmiedebergs Arch Pharmacol 2000;362:116–21.10.1007/s002100000266Search in Google Scholar PubMed
13. UNODC. World Drug Report 2011. Cited 6/5/2012. Available at: http://www.unodc.org/documents/data-and-analysis/WDR2011/World_Drug_Report_2011_ebook.pdf.Search in Google Scholar
14. Jamali B, Ardakani YH, Rouini MR, Foroumadi A, Amidi S, Aghdam VH, et al. Determination of the role of calcium on instability of neurotoxic metabolite of Ecstasy by HPTLC-mass. Daru 2013;21:9.10.1186/2008-2231-21-9Search in Google Scholar PubMed PubMed Central
15. Mehrpour O. Methamphetamin abuse a new concern in Iran. Daru 2012;20:73.10.1186/2008-2231-20-73Search in Google Scholar PubMed
16. Khajeamiri AR, Kobarfard F, Ahmadkhaniha R, Mostashari G. Profiling of Ecstasy tablets seized in Iran. Iran J Pharm Res 2011;10:211–20.Search in Google Scholar PubMed
17. Mahdy T, El-Shihi TH, Emara MM, Chericoni S, Giusiani M, Giorgi M. Development and validation of a new GC-MS method for the detection of tramadol, O-desmethyltramadol, 6-acetylmorphine and morphine in blood, brain, liver and kidney of Wistar rats treated with the combination of heroin and tramadol. J Anal Toxicol 2012;36:548–59.10.1093/jat/bks069Search in Google Scholar PubMed
18. Green AR, Mechan AO, Elliott JM, O’Shea E, Colado MI. The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”). Pharmacol Rev 2003;55:463–508.10.1124/pr.55.3.3Search in Google Scholar PubMed
19. Felim A, Neudörffer A, Monnet FP, Largeron M. Environmentally friendly expeditious one-pot electrochemical synthesis of bis-catechol-thioether metabolites of Ecstasy: in vitro neurotoxic effects in the rat hippocampus. Int J Electrochem Sci 2008;3:266–81.Search in Google Scholar
20. Van LM, Swales J, Hammond C, Wilson C, Hargreaves JA, Rostami-Hodjegan A. Kinetics of the time-dependent inactivation of CYP2D6 in cryopreserved human hepatocytes by methylenedioxymethamphetamine (MDMA). Eur J Pharm Sci 2007;31:53–61.10.1016/j.ejps.2007.02.005Search in Google Scholar PubMed
21. Heydari A, Yeo KR, Lennard MS, Ellis SW, Tucker GT, Rostami-Hodjegan A. Mechanism-based inactivation of CYP2D6 by methylenedioxymethamphetamine. Drug Metab Dispos 2004;32:1213–7.10.1124/dmd.104.001180Search in Google Scholar PubMed
22. Guengerich FP. Comparisons of catalytic selectivity of cytochrome P450 subfamily enzymes from different species. Chem Biol Interact 1997;106:161–82.10.1016/S0009-2797(97)00068-9Search in Google Scholar PubMed
23. Imaoka S, Yamada T, Hiroi T, Hayashi K, Sakaki T, Yabusaki Y, et al. Multiple forms of human P450 expressed in Saccharomyces cerevisiae. Systematic characterization and comparison with those of the rat. Biochem Pharmacol 1996;51:1041–50.10.1016/0006-2952(96)00052-4Search in Google Scholar PubMed
24. Thrivikraman KV, Huot RL, Plotsky PM. Jugular vein catheterization for repeated blood sampling in the unrestrained conscious rat. Brain Res Brain Res Protoc 2002;10:84–94.10.1016/S1385-299X(02)00185-XSearch in Google Scholar PubMed
25. Cheze M, Deveaux M, Martin C, Lhermitte M, Pepin G. Simultaneous analysis of six amphetamines and analogues in hair, blood and urine by LC-ESI-MS/MS. Application to the determination of MDMA after low Ecstasy intake. Forensic Sci Int 2007;170:100–4.10.1016/j.forsciint.2007.02.033Search in Google Scholar PubMed
26. FDA Guidance for Industry. Bioanalytical Method Validation 2001. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070107.pdf.Search in Google Scholar
27. Musshoff F, Madea B. Fatality due to ingestion of tramadol alone. Forensic Sci Int 2001;116:197–9.10.1016/S0379-0738(00)00374-1Search in Google Scholar PubMed
28. Willaschek C, Wolter E, Buchhorn R. Tramadol withdrawal in a neonate after long-term analgesic treatment of the mother. Eur J Clin Pharmacol 2009;65:429–30.10.1007/s00228-008-0598-zSearch in Google Scholar PubMed
29. Pothiawala S, Ponampalam R. Tramadol overdose: a case report. Proc Singapore Healthc 2011;20:219–23.10.1177/201010581102000311Search in Google Scholar
30. Tzvetkov MV, Saadatmand AR, Lotsch J, Tegeder I, Stingl JC, Brockmoller J. Genetically polymorphic OCT1: another piece in the puzzle of the variable pharmacokinetics and pharmacodynamics of the opioidergic drug tramadol. Clin Pharmacol Ther 2011;90:143–50.10.1038/clpt.2011.56Search in Google Scholar PubMed
31. Amphoux A, Vialou V, Drescher E, Bruss M, Mannoury La Cour C, Rochat C, et al. Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology 2006;50:941–52.10.1016/j.neuropharm.2006.01.005Search in Google Scholar PubMed
32. Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP, et al. Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 2001;29:1146–55.Search in Google Scholar PubMed
33. Yubero-Lahoz S, Pardo R, Farre M, O’Mahony B, Torrens M, Mustata C, et al. Sex differences in 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy)-induced cytochrome P450 2D6 inhibition in humans. Clin Pharmacokinet 2011;50:319–29.10.2165/11584550-000000000-00000Search in Google Scholar PubMed
34. Fonsart J, Menet MC, Debray M, Hirt D, Noble F, Scherrmann JM, et al. Sprague-Dawley rats display sex-linked differences in the pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolite-methylenedioxyamphetamine (MDA). Toxicol Appl Pharmacol 2009;241:339–47.10.1016/j.taap.2009.09.008Search in Google Scholar PubMed
35. de la Torre R, Farre M, Roset PN, Pizarro N, Abanades S, Segura M, et al. Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Ther Drug Monit 2004;26:137–44.10.1097/00007691-200404000-00009Search in Google Scholar PubMed
36. 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;29:569–74.10.1016/j.jevs.2009.05.010Search in Google Scholar
37. Stamer UM, 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;82:41–7.10.1038/sj.clpt.6100152Search in Google Scholar PubMed
©2017 Walter de Gruyter GmbH, Berlin/Boston
