Detection of Metabolites of the New Synthetic Cannabinoid MDMB-4en-PINACA in Human Urine by Liquid and Gas Chromato-Mass Spectrometry Methods

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Resumo

MDMB-4en-PINACA belongs to the new synthetic psychoactive compounds that have been distributed in Russia since at least 2020 and is highly active against the human cannabinoid receptor CB1. Its distinctive feature is the presence of an N-pentene residue, which is rare for this group of compounds. The significant hydrophobicity of MDMB-4en-PINACA, like most other synthetic cannabimimetics on the world market, results in almost complete biotransformation of the parent compound and very low levels in urine. Hence the need to identify its metabolites, the detection of which would indicate the use of MDMB-4en-PINACA. To solve this problem we used gas and liquid chromatography-mass spectrometry methods, including high-performance chromatography-mass spectrometry with a quadrupole time-of-flight detector and a three-dimensional ion trap detector equipped with an electrospray ionization source. A number of putative metabolites of MDMB-4en-PINACA in human urine were identified as products of hydrolysis, mono- and dihydroxylation, reduction, dihydrodiol formation, carboxylation, carboxylation with elimination of methylene group, N-dealkylation and combinations of these processes. A number of metabolites were found in the form of glucuronides. The obtained results are in good agreement with literature data. For routine chemical-toxicological and forensic chemical analysis of urine by gas chromatography-mass spectrometry is optimal to search for products of hydrolysis, dihydroxylation and dihydrodiol formation, while when using liquid chromatography-mass spectrometry is also recommended detection of glucuronides of hydrolysis products and dihydrodiol formation.

Sobre autores

I. Nikolaev

Republican narcological dispensary № 1

Email: chrzond4250@yandex.ru
Rússia, Ufa

A. Bajkova

Republican narcological dispensary № 1

Email: chrzond4250@yandex.ru
Rússia, Ufa

E. Galeeva

Republican narcological dispensary № 1

Email: chrzond4250@yandex.ru
Rússia, Ufa

A. Grigoryev

Ministry of Defense of the Russian Federation

Autor responsável pela correspondência
Email: chrzond4250@yandex.ru

“27 Scientific Centre”

Rússia, Moscow

Bibliografia

  1. The cannabinoid receptors / Ed. Reggio P.H. New York: Humana Press, 2009. 396 p.
  2. Mustata C., Torrens M., Pardo R., The Psychonaut web mapping group, Farre, M. Spice drugs: cannabinoids as a new designer drugs // Adicciones. 2009. V. 21. № 3. P. 181.
  3. European Drug Report 2023: Trends and Developments. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), 2022. https://www.emcdda.europa.eu/publications/edr/trends-developments/2022_en (дата обращения 20.05.2024).
  4. Assi S., Marshall D., Bersani F.S., Corazza O. Uses, effects and toxicity of synthetic cannabinoids from the perspective of people with lived experiences // J. Psychoactive Drugs. 2020. V. 52. № 3. P. 237. https://doi.org/10.1080/02791072.2020.1723748
  5. Giorgetti A., Busardò F.P., Tittarelli R., Auwärter V., Giorgetti R. Post-mortem toxicology: A systematic review of death cases involving synthetic cannabinoid receptor agonists // Front. Psychiatry. 2020. V. 11. P. 464. https://doi.org/10.3389/fpsyt.2020.00464
  6. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) initial report on the new psychoactive substance methyl 3,3-dimethyl-2-(1-(pent-4-enyl)-1H-indazole-3-carboxamido)butanoate (MDMB-4en-PINACA). Luxembourg: Publications Office of the European Union, 2020. https://www.emcdda.europa.eu/system/files/publications/13363/emcdda-initial-report-MDMB-4en-PINACA.pdf (дата обращения 20.05.2024).
  7. World Health Organization. Critical Review Report: MDMB-4en-PINACA. Geneva, 2020. https://www.who.int/docs/default-source/controlled-substances/43rd-ecdd/mdmb-4en-pinaca-review-2020.pdf?sfvrsn=5cd6e97e_4 (дата обращения 20.05.2024).
  8. Norman C., Walker G., McKirdy B., McDonald C., Fletcher D., Antonides L.H. et al. Detection and quantitation of synthetic cannabinoid receptor agonists in infused papers from prisons in a constantly evolving illicit market // Drug Test. Anal. 2020. V. 12. № 4. P. 538. https://doi.org/10.1002/dta.2767
  9. Krotulski A.J., Cannaert A., Stove C., Logan B.L. The next generation of synthetic cannabinoids: Detection, activity, and potential toxicity of pent‐4en and but‐3en analogues including MDMB‐4en‐PINACA // Drug Test. Anal. 2021. V. 13. № 2. P. 427. https://doi.org/10.1002/dta.2935
  10. Diao X., Huestis M.A. Approaches, challenges and advances in metabolism of new synthetic cannabinoids and identification of optimal urinary marker metabolites // Clin. Pharmacol. Ther. 2017. V. 101. № 2. P. 239. https://doi.org/10.1002/cpt.534
  11. Leong H.S., Watanabe S., Kuzhiumparambil U., Fong C.Y., Moy H.Y., Yao Y.J. et al. Monitoring metabolism of synthetic cannabinoid 4F-MDMB-BINACA via high-resolution mass spectrometry assessed in cultured hepatoma cell line, fungus, liver microsomes and confirmed using urine samples // Forensic Toxicol. 2021. V. 39. P. 198. https://doi.org/10.1007/s11419-020-00562-7
  12. Franz F., Jechle H., Wilde M., Angerer V., Huppertz L.M., Longworth M. et al. Structure-metabolism relationships of valine and tert-leucine-derived synthetic cannabinoid receptor agonists: a systematic comparison of the in vitro phase I metabolism using pooled human liver microsomes and high-resolution mass spectrometry // Forensic Toxicol. 2019. V. 37. P. 316. https://doi.org/10.1007/s1141 9-018-00462–x
  13. Jang M., Yang W., Choi H., Chang H., Lee S., Kim E., Chung H. Monitoring of urinary metabolites of JWH-018 and JWH-073 in legal cases // Forensic Sci. Int. 2013. V. 231. P. 13. https://doi.org/10.1016/j.forsciint.2013.03.053
  14. Mogler L., Franz F., Wilde M., Huppertz L.M., Halter S., Angerer V. et al. Phase I metabolism of the carbazole-derived synthetic cannabinoids EG-018, EG-2201, and MDMB-CHMCZCA and detection in human urine samples // Drug Test. Anal. 2018. V. 10. № 9. P. 1417. https://doi.org/10.1016/10.1002/dta.2398
  15. Григорьев А.М., Крупина Н.А., Никитин Е.В., Грибкова С.Е., Калашников В.А. Выявление метаболитов нового синтетического каннабиноида MMB-022 в моделях in vivo и in vitro методом жидкостной хромато-масс-спектрометрии // Масс-спектрометрия. 2020. Т. 17. № 3. С. 151. https://doi.org/10.25703/MS.2020.17.33
  16. Watanabe S., Wu X., Dahlen J., Konradsson P., Vikingsson S., Kronstrand R., Gréen H. Metabolism of MMB022 and identification of dihydrodiol formation in vitro using synthesised standards // Drug Test. Anal. 2020. V. 12. № 10. P. 1432. https://doi.org/10.1002/dta.2888
  17. Watanabe S., Vikingsson S., Åstrand A., Gréen H., Kronstrand R. Biotransformation of the New synthetic cannabinoid with an alkene, MDMB-4en-PINACA, by human hepatocytes, human liver microsomes, and human urine and blood // AAPS J. 2019. V. 22. № 1. P. 13. https://doi.org/10.1208/s12248-019-0381-3
  18. Ozturk Y.E., Yeter O. In vitro phase i metabolism of the recently emerged synthetic MDMB-4en-PINACA and its detection in human urine samples // J. Anal. Toxicol. 2020. V. 44. № 9. P. 976. https://doi.org/10.1093/jat/bkaa017
  19. Liying Z., Min S., Baohua S., Hang C., Xin W., Hongxiao D. et al. Application of a UPLC-MS/MS method for quantitative analysis of 29 synthetic cannabinoids and their metabolites, such as ADB-BUTINACA and MDMB-4en-PINACA in human hair in real cases // Forensic Sci. Int. 2022. V. 331. Article 111139. https://doi.org/10.1016/j.forsciint.2021.111139
  20. Kronstrand R., Norman C., Vikingsson S., Biemans A., Crespo B.V., Edwards D. et al. The metabolism of the synthetic cannabinoids ADB-BUTINACA and ADB-4en-PINACA and their detection in forensic toxicology casework and infused papers seized in prisons // Drug Test. Anal. 2022. V. 14. № 4. P. 634. https://doi.org/10.1002/dta.3203
  21. March R.E. An introduction to quadrupole ion trap mass spectrometry // J. Mass Spectrom. 1997. V. 32. № 4. P. 351.
  22. Bruker Daltonics Toxtyper™ 2012. https://www.bruker.com/en/products-and-solutions/mass-spectrometry/ms-solutions/toxtyper.html (дата обращения 20.05.2024).
  23. Wissenbach D.K., Meyer M.R., Remane D., Philipp A.A., Weber A.A., Maurer H.H. Drugs of abuse screening in urine as part of a metabolite-based LC-MSn screening concept // Anal. Bioanal. Chem. 2011. V. 400. № 10. P. 3481. https://doi.org/10.1007/s00216-010-4398-9
  24. Граник В.Г. Метаболизм экзогенных соединений. Лекарственные средства и другие ксенобиотики. М.: Вузовская книга, 2015. 526 с.

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