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Metabolism of ADB-4en-PINACA in Zebrafish and Rat Liver Microsomes Determined by Liquid Chromatography–High Resolution Mass Spectrometry

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Abstract

Metabolic models can be useful for rapid identification of suitable analytical targets to aid in the detection of new psychoactive substances (NPS) in human biological samples. In vitro and in vivo metabolic studies of the synthetic cannabinoid ADB-4en-PINACA were carried out using zebrafish and rat liver microsome models. Seventeen phase-I metabolites, including seventeen metabolites generated from rat liver microsomes and fourteen metabolites from zebrafish, were identified and structurally characterized by liquid chromatography–high resolution mass spectrometry. The main metabolic pathways of the phase-I metabolism included hydroxylation, N-dealkylation, amide hydrolysis, ketone formation from the t-butyl and aliphatic chains, oxidation of the N-double-bond, amide hydrolysis combined with dehydrogenation, and amide hydrolysis followed by hydroxylation, as well as dehydrogenation and N-dealkylation. Hydroxylation (M3), ketone (M10), and dihydrodiol (M15) metabolites can be recommended as metabolic markers for ADB-4en-PINACA. These findings identify the zebrafish model as a promising tool for elucidating the metabolism of NPS.

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REFERENCES

  1. United Nations Office on Drugs and Crime (UNODC), World Drug Report 2013. https://www.unodc.org/wdr2013/en/nps.html Accessed July 14, 2021.

  2. Zacca, J.J., Giudice, G.H., Souza, M.P., Caldas, L.N.B., Vieira, M.L., and Machado, A.H.L., J. Chromatogr. A, 2021, vol. 1636, 461783. https://doi.org/10.1016/j.chroma.2020.461783

    Article  CAS  PubMed  Google Scholar 

  3. Carlier, J., Diao, X., Scheidweiler, K.B., and Huestis, M.A., Clin. Chem., 2017, vol. 63, no. 5, p. 1008. https://doi.org/10.1373/clinchem.2016.267575

    Article  CAS  PubMed  Google Scholar 

  4. Lo Faro, A.F., Di Trana, A., La Maida, N., Tagliabracci, A., Giorgetti, R., and Busardò, F.P., J. Pharm. Biomed. Anal., 2020, vol. 179, 112945. https://doi.org/10.1016/j.jpba.2019.112945

  5. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). European Drug Report 2020: Trends and Developments. https://www.emcdda.europa.eu/publications/edr/trendsdevelopments/2020_en.

  6. United Nations Office on Drugs and Crime (UNODC), Current NPS Threats, vol. 1, March 2019. https://www.unodc.org/pdf/opioids-crisis/Current_NPS_Threats_-_Volume_I.pdf.

  7. United Nations Office on Drugs and Crime (UNODC). The Challenge of New Psychoactive Sustances—Global SMART Programme, 2013. https://www.unodc.org/documents/scientific/NPS_Report.pdf.

  8. Ausloos, P., Clifton, C.L., Lias, S.G., Mikaya, A.I., Stein, S.E., Tchekhovskoi, D.V., Sparkman, O.D., Zaikin, V., and Zhu, D., J. Am. Soc. Mass Spectrom., 1999, vol. 10, no. 4, p. 287. https://doi.org/10.1016/S1044-0305(98)00159-7

    Article  CAS  PubMed  Google Scholar 

  9. Castaing-Cordier, T., Ladroue, V., Besacier, F., Bulete, A., Jacquemin, D., Giraudeau, P., and Farjon, J., Forensic Sci. Int., 2021, vol. 321, 110718. https://doi.org/10.1016/j.forsciint.2021.110718

    Article  CAS  PubMed  Google Scholar 

  10. Diao, X. and Huestis, M.A., Clin. Pharmacol. Ther., 2017, vol. 101, no. 2, p. 239. https://doi.org/10.1002/cpt.534

    Article  CAS  PubMed  Google Scholar 

  11. Yue, L., Xiang, P., Shen, B., Xu, D., Song, F., and Yan, H., Drug Test. Anal., 2021, vol. 13, no. 6, p. 1223. https://doi.org/10.1002/dta.3019

    Article  CAS  PubMed  Google Scholar 

  12. Martinotti, G., Santacroce, R., Papanti, D., Elgharably, Y., Prilutskaya, M., and Corazza, O., CNS Neurol. Disord.: Drug Targets, 2017, vol. 16, no. 5, p. 567. https://doi.org/10.2174/1871527316666170413101839

    Article  CAS  Google Scholar 

  13. Cannaert, A., Vandeputte, M., Wille, S.M.R., and Stove, C.P., Crit. Rev. Toxicol., 2019, vol. 49, no. 2, p. 95. https://doi.org/10.1080/10408444.2019.1576588

    Article  CAS  PubMed  Google Scholar 

  14. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), 2019b. European Drug Report 2019: Trends and Developments. http://www.emcdda.europa.eu/edr2019_en.

  15. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). European Drug Report 2018: Trends and Developments, Luxembourg: Publ. Office of the European Union, . https://www.unodc.org/documents/scientific/Regional_Overview_Europe.pdf.

  16. Seely, K.A., Lapoint, J., Moran, J.H., and Fattore, L., Prog. Neuropsychopharmacol. Biol. Psychiatry, 2012, vol. 39, no. 2, p. 234. https://doi.org/10.1016/j.pnpbp.2012.04.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Grafinger, K.E., Mandhair, H.K., Broillet, A., Gertsch, J., and Weinmann, W., Forensic Toxicol., 2019, vol. 37, p. 398. https://doi.org/10.1007/s11419-019-00474-1

    Article  CAS  Google Scholar 

  18. Wiley, J.L., Marusich, J.A., and Huffman, J.W., Life Sci., 2014, vol. 97, no. 1, p. 55. https://doi.org/10.1016/j.lfs.2013.09.011

    Article  CAS  PubMed  Google Scholar 

  19. Castaneto, M.S., Gorelick, D.A., Desrosiers, N.A., Hartman, R.L., Pirard, S., and Huestis, M.A., Drug Alcohol Depend., 2014, vol. 144, p. 12. https://doi.org/10.1016/j.drugalcdep.2014.08.005

    Article  CAS  PubMed  Google Scholar 

  20. Kemp, A.M., Clark, M.S., Dobbs, T., Galli, R., Sherman, J., and Cox, R., Am. J. Med., 2016, vol. 129, no. 3, p. 240. https://doi.org/10.1016/j.amjmed.2015.10.008

    Article  CAS  PubMed  Google Scholar 

  21. Elsohly, M.A., Gul, W., Wanas, A.S., Radwan, M.M., Life Sci., 2014, vol. 97, no. 1, p. 78. https://doi.org/10.1016/j.lfs.2013.12.212

    Article  CAS  PubMed  Google Scholar 

  22. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Understanding the 'Spice' phenomenon. http://www.emcdda.europa.eu/system/files/publications/537/Spice-Thematic-paper-final-version.pdf.

  23. Pertwee, R.G., Br. J. Pharmacol., 2008, vol. 153, no. 2, p. 199. https://doi.org/10.1038/sj.bjp.0707442

    Article  CAS  PubMed  Google Scholar 

  24. Hill, S.L., Najafi, J., Dunn, M., Acheampong, P., Kamour, A., Grundlingh, J, Blain, P.G., and Thomas, S.H.L., Clin. Toxicol. (Phila), 2016, vol. 54, no. 8, p. 638. https://doi.org/10.1080/15563650.2016.1190980

    Article  CAS  Google Scholar 

  25. Tait, R.J., Caldicott, D., Mountain, D., Hill, S.L., and Lenton, S., Clin. Toxicol. (Phila), 2016, vol. 54, no. 1, p. 1. https://doi.org/10.3109/15563650.2015.1110590

    Article  CAS  Google Scholar 

  26. Fantegrossi, W.E., Moran, J.H., Radominska-Pandya, A., and Prather, P.L., Life Sci., 2014, vol. 97, no. 1, p. 45. https://doi.org/10.1016/j.lfs.2013.09.017

    Article  CAS  PubMed  Google Scholar 

  27. Hermanns-Clausen, M., Kneisel, S., Szabo, B., and Auwärter, V., Addiction, 2013, vol. 108, no. 3, p. 534. doi. 2012. 04078.xhttps://doi.org/10.1111/j.1360-0443

  28. Abouchedid, R., Hudson, S., Thurtle, N., Yamamoto, T., Ho, J.H., Bailey, G., Wood, M., Sadones, N., Stove, C.P., Dines, A., Archer, J.R.H., Wood, D.M., and Dargan, P.I., Clin. Toxicol. (Phila), 2017, vol. 55, no. 5, p. 338. https://doi.org/10.1080/15563650.2017.1287373

    Article  CAS  Google Scholar 

  29. Adamowicz, P., Forensic Sci. Int., 2016, vol. 261, e5. https://doi.org/10.1016/j.forsciint.2016.02.024

    Article  CAS  PubMed  Google Scholar 

  30. Cooper, Z.D., Curr. Psychiatry Rep., 2016, vol. 18, no. 5, p. 52. https://doi.org/10.1007/s11920-016-0694-1

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lin, H., Zeng, X., Wang, Q., Yinnan, L., Bin, S., Ying, W., and Wang, H., Forensic Toxicol., 2019, vol. 38, no. 1, p. 216. https://doi.org/10.1007/s11419-019-00510-0

    Article  CAS  Google Scholar 

  32. Diao, X. and Huestis, M.A., Front. Chem., 2019, vol. 7, 109. https://doi.org/10.3389/fchem.2019.00109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Thomsen, R., Nielsen, L.M., Holm, N.B., Rasmussen, H.B., and Linnet, K., Drug Test. Anal., 2015, vol. 7, no. 7, p. 565. https://doi.org/10.1002/dta.1731

    Article  CAS  PubMed  Google Scholar 

  34. Kong, T.Y., Kim, J.H., Kim, D.K., and Lee, H.S., Arch. Pharm. Res., 2018, vol. 41, no. 7, p. 691. https://doi.org/10.1007/s12272-018-1055-x

    Article  CAS  PubMed  Google Scholar 

  35. Richter, L.H.J., Maurer, H.H., and Meyer, M.R., Toxicol. Lett., 2017, vol. 280, p. 142. https://doi.org/10.1016/j.toxlet.2017.07.901

    Article  CAS  PubMed  Google Scholar 

  36. Kronstrand, R., Norman, C., Vikingsson, S., Biemans, A., Crespo, B.V., Edwards, D., Fletcher, D., Gilbert, N., Persson, M., Reid, R., Semenova, O., Al Teneiji, F., Wu, X., Dahlén, J., NicDaéid, N., Tarbah, F., Sutcliffe, O.B., McKenzie, C., and Gréen, H., Drug Test. Anal., 2022, vol. 14, no. 4, p. 634. https://doi.org/10.1002/dta.3203

    Article  CAS  PubMed  Google Scholar 

  37. Goldsmith, P., Curr. Opin. Pharmacol., 2004, vol. 4, no. 5, p. 504. https://doi.org/10.1016/j.coph.2004.04.005

    Article  CAS  PubMed  Google Scholar 

  38. Bruni, G., Rennekamp, A.J., Velenich, A., McCarroll, M., Gendelev, L., Fertsch, E., Taylor, J., Lakhani, P., Lensen, D., Evron, T., Lorello, P.J., Huang, X.-P., Kolczewski, S., Carey, G., Caldarone, B.J., Prinssen, E., Roth, B.L., Keiser, M.J., Peterson, R.T., and Kokel, D., Nat. Chem. Biol., 2016, vol. 12, no. 7, p. 559. https://doi.org/10.1038/nchembio.2097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Anderson, J.L., Carten, J.D., and Farber, S.A., Methods Cell. Biol., 2011, vol. 101, p. 111. https://doi.org/10.1016/B978-0-12-387036-0.00005-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bresolin, T., de Freitas, R.M., and Celso Dias Bainy, A., Comp. Biochem. Physiol., Part C: Toxicol. Pharmacol., 2005, vol. 140, nos. 3–4, p. 403. https://doi.org/10.1016/j.cca.2005.04.003

    Article  CAS  Google Scholar 

  41. Jones, H.S., Panter, G.H., Hutchinson, T., and Chipman, K.J., Toxicology, 2008, vol. 253, nos. 1–3, p. 12. https://doi.org/10.1016/j.tox.2008.07.011

    Article  CAS  Google Scholar 

  42. de Souza Anselmo, C., Sardela, V.F., Matias, B.F., de Carvalho, A.R., de Sousa, V.P., Pereira, H.M.G., and de Aquino Neto, F.R., Drug Test. Anal., 2017, vol. 9, nos. 11–12, p. 1685. https://doi.org/10.1016/j.tox.2008.07.011

    Article  CAS  PubMed  Google Scholar 

  43. Truver, M.T., Watanabe, S., Åstrand, A., Vikingsson, S., Green, H., Swortwood, M.J., and Kronstrand, R., Drug Test. Anal., 2020, vol. 12, no. 1, p. 127. https://doi.org/10.1002/dta.2688

    Article  CAS  PubMed  Google Scholar 

  44. Krotulski, A.J., Mohr, A.L.A., Kacinko, S.L., Fogarty, M.F., Shuda, S.A., Diamond, F.X., Kinney, W.A., Menendez, M.J., and Logan, B.K., J. Forensic Sci., 2019, vol. 64, no. 5, p. 1451. https://doi.org/10.1111/1556-4029.14101

    Article  CAS  PubMed  Google Scholar 

  45. Haschimi, B., Mogler, L., Halter, S., Giorgetti, A., Schwarze, B., Westphal, F., Fischmann, S., and Auwärter, V., Drug Test. Anal., 2019, vol. 11, no. 9, p. 1377. https://doi.org/10.1002/dta.2666

    Article  CAS  PubMed  Google Scholar 

  46. Lie, W., Cheong, E.J.Y., Goh, E.M.L., Moy, H.Y., Cannaert, A., Stove, C.P., and Chan, E.C.Y., Arch. Toxicol., 2021, vol. 95, no. 2, p. 489. https://doi.org/10.1007/s00204-020-02948-3

    Article  CAS  PubMed  Google Scholar 

  47. Yeter, E.O. and Yeter, O., J. Anal. Toxicol., 2021, vol. 44, no. 9, p. 976. https://doi.org/10.1093/jat/bkaa017

    Article  CAS  PubMed  Google Scholar 

  48. Watanabe, S., Vikingsson, S., Åstrand, A., Gréen, H., and Kronstrand, R., AAPS J., 2019, vol. 22, no. 1, p. 13. https://doi.org/10.1208/s12248-019-0381-3

    Article  CAS  PubMed  Google Scholar 

  49. Wohlfarth, A., Castaneto, M.S., Zhu, M., Pang, S., Scheidweiler, K.B., Kronstrand, R., and Huestis, M.A., AAPS J., 2015, vol. 17, p. 660. https://doi.org/10.1208/s12248-015-9721-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Castaneto, M., Wohlfarth, A., Pang, S., Zhu, M., Scheidweiler, K.B., Kronstrand, R., and Huestis, M.A., Forensic Toxicol., 2015, vol. 33, p. 295. https://doi.org/10.1002/dta.2659

    Article  CAS  Google Scholar 

  51. Carlier, J., Diao, X., Wohlfarth, A., Scheidweiler, K., and Huestis, M.A., Curr Neuropharmacol., 2017, vol. 15, no. 5, p. 682. https://doi.org/10.2174/1570159X15666161108123419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Richter, L.H.J., Maurer, H.H., and Meyer, M.R., Drug Test. Anal., 2019, vol. 11, no. 2, p. 305. https://doi.org/10.1002/dta.2493

    Article  CAS  PubMed  Google Scholar 

  53. Yeter, O. and Ozturk, Y.E., Drug Test. Anal., 2019, vol. 11, no. 6, p. 847. https://doi.org/10.1002/dta.2566

    Article  CAS  PubMed  Google Scholar 

  54. Sohlenius-Sternbeck, A.K., Chelpin, H.V., Orzechowski, A., and Halldin, M.M., Drug Metab. Dispos., 2000, vol. 28, no. 6, p. 695.

    CAS  PubMed  Google Scholar 

  55. Diao, X., Deng, P., Xie, C., Li, X., Zhong, D., Zhang, Y., and Chen, X., Drug Metab. Dispos., 2013, vol. 41, no. 2, p. 430. https://doi.org/10.1124/dmd.112.04

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the Science and Technology Commission of Shanghai Municipality (nos. 19ZR1458800, 21DZ2270800, and 19DZ2292700), the National Natural Science Foundation of China (no. 81871531).

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Authors and Affiliations

  1. Department of Forensic Toxicology, Academy of Forensic Science, Shanghai, China

    Xinze Liu, Wei Liu, Ping Xiang, Yan Shi, Linna Yue & Hui Yan

  2. College of pharmacy, China Pharmaceutical University, Nanjing, China

    Xinze Liu & Taijun Hang

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Xinze Liu, Liu, W., Xiang, P. et al. Metabolism of ADB-4en-PINACA in Zebrafish and Rat Liver Microsomes Determined by Liquid Chromatography–High Resolution Mass Spectrometry. J Anal Chem 77, 1036–1046 (2022). https://doi.org/10.1134/S1061934822080184

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