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Journal of veterinary pharmacology and therapeutics2021; 44(5); 842-849; doi: 10.1111/jvp.12998

Pharmacokinetic properties of metamizole active metabolites in Northeastern Brazilian donkeys (Equus asinus).

Abstract: Metamizole (MT), also known as dipyrone, is an analgesic and antipyretic drug labeled for use in humans and domestic animals in some countries. As with other drugs, the administration of MT in donkeys is based on studies carried out with horses. In the present report, we aimed to determine the pharmacokinetics of the two main metamizole active metabolites (N-methyl-4-aminoantipyrine [MAA] and 4-aminoantipyrine [AA]) following 10 (M ) and 25 mg/kg (M ) IV metamizole doses in Northeast Brazilian donkeys (n = 10). Blood was collected at predetermined times within over 48 h; MAA and AA plasma concentrations were determined by a validated LC-MS/MS method. The metabolites were quantifiable in the M until 12 h and M until 24 h after drug administration. As expected, AUC , AUC and C demonstrated significant differences increases in metamizole metabolites profiles when groups were compared. No adverse effects were observed. This study indicates the need for an extremely sensitive analytical method to adequately characterize the pharmacokinetics of active metabolites of MT, MAA, and AA. In conclusion, the method developed in this research was able to measure the active metabolites of metamizole and with that it was possible to establish their pharmacokinetic profile. Furthermore, after projection of the minimum MAA concentrations, it is possible to infer that the dose of 10 mg/kg will be used on donkeys at 6 h intervals, while the M25 group at 12 h intervals. However, clinical studies are needed to assess this hypothesis.
© 2021 John Wiley & Sons Ltd.
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Publication Date: 2021-07-15 PubMed ID: 34268764DOI: 10.1111/jvp.12998Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article reports on a study aimed at determining the pharmacokinetics of the two main active metabolites of the drug Metamizole in Northeast Brazilian donkeys. The study concluded that an extremely sensitive analytical method is needed to adequately characterize these pharmacokinetics, and clinical studies may be necessary to confirm their application intervals.

Research Context and Objectives

  • The study was conducted in response to the fact that the use of the drug Metamizole (MT), an analgesic and antipyretic drug, in donkeys is based on studies performed on horses, not specifically on donkeys.
  • The researchers aimed to assess the pharmacokinetics of the two main active metabolites of Metamizole, N-methyl-4-aminoantipyrine (MAA) and 4-aminoantipyrine (AA), in Northeast Brazilian donkeys. Pharmacokinetics refers to how the body affects a specific drug after administration.

Research Methodology

  • Two different intravenous doses of Metamizole—10mg/kg and 25mg/kg—were administered to the donkeys (n=10).
  • Blood samples were then collected at predetermined times up to 48 hours after the administration of the drug.
  • The concentrations of MAA and AA in the plasma were determined using a validated LC-MS/MS method, a highly sensitive and specific analytical technique used for quantifying molecules in complex samples.
  • The metabolites were monitored up to 12 hours for the 10mg group and 24 hours for the 25mg group following drug administration.

Results and Observations

  • The researchers noted significant differences and increases in the profiles of the Metamizole metabolites when comparing the two groups.
  • No adverse effects were observed during the study.
  • The authors suggested that due to the intricate behavior of the metabolites, a highly sensitive analytical method is required to adequately characterize the pharmacokinetics of MAA and AA.

Conclusions and Future Research

  • The study successfully established the pharmacokinetic profile of the active metabolites of Metamizole in donkeys, offering a basis for further research and application.
  • The projected minimum concentrations of MAA suggest that a dose of 10mg/kg can potentially be used on donkeys at 6-hour intervals, while a dose of 25mg/kg can be used at 12-hour intervals. These predictions, however, need to be confirmed through clinical studies.

Cite This Article

APA
de Macêdo LB, Mouta AN, Araújo-Silva G, Urizar JTP, de Paula VV. (2021). Pharmacokinetic properties of metamizole active metabolites in Northeastern Brazilian donkeys (Equus asinus). J Vet Pharmacol Ther, 44(5), 842-849. https://doi.org/10.1111/jvp.12998

Publication

Journal of veterinary pharmacology and therapeutics
ISSN: 1365-2885
NlmUniqueID: 7910920
Country: England
Language: English
Volume: 44
Issue: 5
Pages: 842-849

Researcher Affiliations

de Macêdo, Luã B
  • Universidade Federal Rural do Semi Árido, Mossoró, RN, Brazil.
Mouta, Andressa N
  • Universidade Federal Rural do Semi Árido, Mossoró, RN, Brazil.
Araújo-Silva, Gabriel
  • Universidade do Estado do Amapá, Macapá, AP, Brazil.
Urizar, Jose Trinidad P
  • Universidad Autónoma de San Luis Potosí, San Luis Potosí - SLP, Mexico.
de Paula, Valéria V
  • Universidade Federal Rural do Semi Árido, Mossoró, RN, Brazil.

MeSH Terms

  • Ampyrone
  • Animals
  • Chromatography, Liquid / veterinary
  • Dipyrone
  • Equidae
  • Tandem Mass Spectrometry / veterinary

Grant Funding

  • Coordenau00e7u00e3o de Aperfeiu00e7oamento de Pessoal de Nu00edvel Superior

References

This article includes 33 references
  1. Abdel-Rahman SM, Kauffman RE. The integration of pharmacokinetics and pharmacodynamics: Understanding dose-response. Annual Review of Pharmacology and Toxicology 44, 111-136.
    doi: 10.1146/annurev.pharmtox.44.101802.121347google scholar: lookup
  2. ANVISA, BRASIL Agência Nacional de Vigilância Sanitária. Resolução da Diretoria Colegiada-RDC Nº 166. 2017. Available at: http://portal.anvisa.gov.br/
  3. Aupanun S, Laus F, Poapolathep A, Owen H, Vullo C, Faillace V, Giorgi M. Pharmacokinetic assessment of the marker active metabolites 4-Methyl-amino-antipyrine and 4-Acetyl-amino-antipyrine after intravenous and intramuscular injection of metamizole (Dipyrone) in healthy donkeys. Journal of Equine Veterinary Science 47, 55-61.
    doi: 10.1016/j.jevs.2016.08.005google scholar: lookup
  4. Basak GW, Drozd-Sokołowska J, Wiktor-Jedrzejczak W. Update on the incidence of metamizole sodium-induced blood dyscrasias in Poland. Journal of International Medical Research 38(4), 1374-1380.
    doi: 10.1177/147323001003800419google scholar: lookup
  5. Burden F, Thiemann A. Donkeys are different. Journal of Equine Veterinary Science 35(5), 376-382.
    doi: 10.1016/j.jevs.2015.03.005google scholar: lookup
  6. Burmańczuk A, Milczak A, Grabowski T, Osypiuk M, Kowalski C. The using of a piglets as a model for evaluating the dipyrone hematological effects. BMC Veterinary Research 12(1), 263.
    doi: 10.1186/s12917-016-0891-5google scholar: lookup
  7. Campion DP, Dowell FJ. Translating pharmacogenetics and pharmacogenomics to the clinic: progress in human and veterinary medicine. Frontiers in Veterinary Science 6(22), 1-11.
    doi: 10.3389/fvets.2019.00022google scholar: lookup
  8. Chen Q, Hu C, Liu Y, Song R, Zhu W, Zhao H, Nino A, Zhang F, Liu Y. Pharmacokinetics, pharmacodynamics, safety, and tolerability of single-dose denosumab in healthy Chinese volunteers: A randomized, single-blind, placebo-controlled study. PLoS One 13(6), e0197984.
    doi: 10.1371/journal.pone.0197984google scholar: lookup
  9. Domínguez-Ramírez AM, Calzadilla PC, Cortés-Arroyo AR, Hurtado y de la Peña M, López JRM, Gómez-Hernández M, López-Muñoz FJ. High-performance liquid chromatographic assay for metamizol metabolites in rat plasma: Application to pharmacokinetic studies. Journal of Pharmaceutical and Biomedical Analysis 71, 173-178.
    doi: 10.1016/j.jpba.2012.07.029google scholar: lookup
  10. . Committee for Veterinary Medicinal Products - Metamizole - Summary Report (2), EMEA/MRL/878/03 - Final June 2003. EMEA (European Agency for the Evaluation of Medicinal Products) 2003, EMEA, London.
  11. Giorgi M, Aupanun S, Lee H-K, Poapolathep A, Rychshanova R, Vullo C, Faillace V, Laus F. Pharmacokinetic profiles of the active metamizole metabolites in healthy horses. Journal of Veterinary Pharmacology and Therapeutics 40(2), 165-171.
    doi: 10.1111/jvp.12342google scholar: lookup
  12. Giorgi M, De Vito V, Lee HK, Laus F, Kowalski C, Faillace V, Burmańczuk A, Vullo C. Pharmacokinetic investigations of the marker active metabolite-4-methylamino-antipyrin after intravenous and intramuscular injection of metamizole in healthy sheep. Small Ruminant Research 132, 143-146.
    doi: 10.1016/j.smallrumres.2015.10.005google scholar: lookup
  13. Giorgi M, Łebkowska-Wieruszewska B, Lisowski A, Owen H, Poapolathep A, Kim TW, De Vito V. Pharmacokinetic profiles of the active metamizole metabolites after four different routes of administration in healthy dogs. Journal of Veterinary Pharmacology and Therapeutics 41(3), 42-436.
    doi: 10.1111/jvp.12484google scholar: lookup
  14. Grosenbaugh DA, Reinemeyer CR, Figueiredo MD. Pharmacology and therapeutics in donkeys. Equine Veterinary Education 23(10), 523-530.
    doi: 10.1111/j.2042-3292.2011.00291.xgoogle scholar: lookup
  15. Hinz B, Cheremina O, Bachmakov J, Renner B, Zolk O, Fromm MF, Brune K. Dipyrone elicits substantial inhibition of peripheral cyclooxygenases in humans: new insights into the pharmacology of an old analgesic. The FASEB Journal 21(10), 2343-2351.
    doi: 10.1096/fj.06-8061comgoogle scholar: lookup
  16. Imagawa VH, Fantoni DT, Tatarunas AC, Mastrocinque S, Almeida TF, Ferreira F, Posso IP. The use of different doses of metamizol for post-operative analgesia in dogs. Veterinary Anesthesia and Analgesia 38(4), 385-393.
    doi: 10.1111/j.1467-2995.2011.00617.xgoogle scholar: lookup
  17. . Harmonized Tripartite Guideline for Good Clinical Practice ICH E6(R2) Integrated Addedum. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 2016, Geneva.
  18. Jasiecka A, Maślanka T, Jaroszewski JJ. Pharmacological characteristics of metamizole. Polish Journal of Veterinary Sciences 17(1), 207-214.
    doi: 10.2478/pjvs-2014-0030google scholar: lookup
  19. Kim TW, Łebkowska-Wieruszewska B, Sitovs A, Poapolathep A, Owen H, Lisowski A, Abilova Z, Giorgi M. Pharmacokinetic profiles of metamizole (dipyrone) active metabolites in goats and its residues in milk. Journal of Veterinary Pharmacology and Therapeutics 41(5), 699-705.
    doi: 10.1111/jvp.12679google scholar: lookup
  20. Lebkowska-Wieruszewska B, Kim TW, Chea B, Owen H, Poapolathep A, Giorgi M. Pharmacokinetic profiles of the two major active metabolites of metamizole (dipyrone) in cats following three different routes of administration. Journal of Veterinary Pharmacology and Therapeutics 41(2), 334-339.
    doi: 10.1111/jvp.12471google scholar: lookup
  21. Levy M, Zylber-Katz E, Rosenkranz B. Clinical pharmacokinetics of dipyrone and its metabolites. Clinical Pharmacokinetics 28(3), 216-234.
    doi: 10.2165/00003088-199528030-00004google scholar: lookup
  22. Lin JH. Dose-dependent pharmacokinetics: experimental observations and theoretical considerations. Biopharmaceutics & Drug Disposition 15(1), 1-31.
    doi: 10.1002/bdd.2510150102google scholar: lookup
  23. Matthews N, Van Loon JPA M. Anesthesia, sedation, and pain management of donkeys and mules. Veterinary Clinics of North America: Equine Practice 35, 515-527.
    doi: 10.1016/j.cveq.2019.08.007google scholar: lookup
  24. Mealey KL. Breed Differences and Pharmacogenetics. Pharmacotherapeutics for Veterinary Dispensing 95-107.
    doi: 10.1002/9781119404576.ch5google scholar: lookup
  25. Morresey PR, White GW, Poole HM, Hu T, Yin M, Sundman EA. Randomized blinded controlled trial of dipyrone as a treatment for pyrexia in horses. American Journal of Veterinary Research 80(3), 294-299.
    doi: 10.2460/ajvr.80.3.294google scholar: lookup
  26. Mouta AN, de Oliveira Lima I, de Oliveira MGC, Alves LP, de Macêdo LB, Araujo-Silva G, Perez-Urizar J, de Paula VV. Pharmacokinetic properties of tramadol and M1 metabolite in Northeast Brazilian donkeys (Equus asinus). Journal of Veterinary Pharmacology and Therapeutics 1-8.
    doi: 10.1111/jvp.12935google scholar: lookup
  27. Oliveira MGCD, Luna SPL, Nunes TL, Firmino PR, de Lima AGA, Ferreira J, de Paula VV. Postoperative pain behaviour associated with surgical castration in donkeys (Equus asinus). Equine Veterinary Journal 00, 1-6.
    doi: 10.1111/evj.13306google scholar: lookup
  28. Rogosch T, Sinning C, Podlewski A, Watzer B, Schlosburg J, Lichtman AH, Cascio MG, Bisogno T, Di Marzo V, Nüsing R, Imming P. Novel bioactive metabolites of dipyrone (metamizol). Bioorganic & Medicinal Chemistry 20(1), 101-107.
    doi: 10.1016/j.bmc.2011.11.028google scholar: lookup
  29. Schenk SA, Dick F, Herzog C, Eberhardt MJ, Leffler A. Active metabolites of dipyrone induce a redox-dependent activation of the ion channels TRPA1 and TRPV1. Pain Reports 4(3), e720.
    doi: 10.1097/pr9.0000000000000720google scholar: lookup
  30. Taffarel MO, Luna SPL, de Oliveira FA, Cardoso GS, Alonso JDM, Pantoja JC, Brondani JT, Love E, Taylor P, White K, Murrell JC. Refinement and partial validation of the UNESP-Botucatu multidimensional composite pain scale for assessing postoperative pain in horses. BMC Veterinary Research 11(1), 83.
    doi: 10.1186/s12917-015-0395-8google scholar: lookup
  31. Vlahov V, Badian M, Verho M, Bacracheva N. Pharmacokinetics of metamizol metabolites in healthy subjects after a single oral dose of metamizol sodium. European Journal of Clinical Pharmacology 38(1), 61-65.
    doi: 10.1007/bf00314805google scholar: lookup
  32. Zanuzzo FS, Teixeira-Neto FJ, Teixeira LR, Diniz MS, Souza VL, Thomazini CM, Steagall PV. Analgesic and antihyperalgesic effects of dipyrone, meloxicam or a dipyrone-meloxicam combination in bitches undergoing ovariohysterectomy. The Veterinary Journal 205(1), 33-37.
    doi: 10.1016/j.tvjl.2015.05.004google scholar: lookup
  33. Zylber-Katz E, Granit L, Levy M. Plasma protein binding of dipyrone metabolites in man. European Journal of Clinical Pharmacology 29(1), 67-71.
    doi: 10.1007/bf00547371google scholar: lookup

Citations

This article has been cited 2 times.
  1. Mouta AN, Arcoverde KN, Fernandes NS, Passos YDB, Oliveira CVA, Honorato RA, Araujo-Silva G, Paula VV. Pharmacokinetic Profile of Two Active Dipyrone Metabolites, 4-Methylaminoantipyrine (MAA) and 4-Aminoantipyrine (AA), Following Intravenous Administration in Dogs: A Preliminary Study. Animals (Basel) 2025 Jun 5;15(11).
    doi: 10.3390/ani15111666pubmed: 40509132google scholar: lookup
  2. Araújo-Silva G, de Macêdo LB, Mouta AN, de Oliveira MGC, Arcoverde KN, Solon LGS, Perez-Urizar JT, de Paula VV. Tramadol and M1 Bioavailability Induced by Metamizole Co-Administration in Donkeys (Equus asinus). Animals (Basel) 2024 Mar 17;14(6).
    doi: 10.3390/ani14060929pubmed: 38540027google scholar: lookup
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