In vitro metabolic profiling and structure–metabolism relationships of substituted acetyl fentanyl-type new psychoactive substances

Armenian P, Vo KT, Barr-Walker J, Lynch KL (2018) Fentanyl, fentanyl analogs and novel synthetic opioids: a comprehensive review. Neuropharmacology 134:121–132. https://doi.org/10.1016/j.neuropharm.2017.10.016

Article  PubMed  CAS  Google Scholar 

Baciocchi E, Bietti M, Gerini MF, Lanzalunga O (2005) Electron-transfer mechanism in the N-demethylation of N,N-dimethylanilines by the phthalimide-N-oxyl radical. J Org Chem 70(13):5144–5149. https://doi.org/10.1021/jo0503916

Article  PubMed  CAS  Google Scholar 

Bergh MS-S, Bogen IL, Nerem E, Wohlfarth A, Wilson SR, Øiestad ÅML (2021) Discovering the major metabolites of the three novel fentanyl analogues 3-methylcrotonylfentanyl, furanylbenzylfentanyl, and 4-fluorocyclopropylbenzylfentanyl for forensic case work. Forensic Toxicol 39(1):167–178. https://doi.org/10.1007/s11419-020-00560-9

Article  CAS  Google Scholar 

Brunetti P, Pirani F, Carlier J, Giorgetti R, Busardò FP, Lo Faro AF (2021) A 2017–2019 update on acute intoxications and fatalities from illicit fentanyl and analogs. J Anal Toxicol 45(6):537–554. https://doi.org/10.1093/jat/bkaa115

Article  PubMed  CAS  Google Scholar 

Chen H, de Groot MJ, Vermeulen NPE, Hanzlik RP (1997) Oxidative N-dealkylation of p-cyclopropyl-N, N-dimethylaniline. A substituent effect on a radical-clock reaction rationalized by ab initio calculations on radical cation intermediates. J Organic Chem 62(23):8227–8230. https://doi.org/10.1021/jo9709209

Article  CAS  Google Scholar 

Colon-Berezin C, Nolan ML, Blachman-Forshay J, Paone D (2019) Overdose deaths involving fentanyl and fentanyl analogs — New York City, 2000–2017. MMWR Morb Mortal Wkly Rep 68(2):37–40. https://doi.org/10.15585/mmwr.mm6802a3

Article  PubMed  PubMed Central  Google Scholar 

Cooman T, Hoover B, Sauvé B et al (2022) The metabolism of valerylfentanyl using human liver microsomes and zebrafish larvae. Drug Test Anal 14(6):1116–1129. https://doi.org/10.1002/dta.3233

Article  PubMed  CAS  Google Scholar 

EMCDDA (2023) European Drug Report 2023: New Psychoactive Substances. https://www.emcdda.europa.eu/publications/european-drug-report/2023/new-psychoactive-substances_en

Feasel MG, Wohlfarth A, Nilles JM, Pang S, Kristovich RL, Huestis MA (2016) Metabolism of carfentanil, an ultra-potent opioid, in human liver microsomes and human hepatocytes by high-resolution mass spectrometry. AAPS J 18(6):1489–1499. https://doi.org/10.1208/s12248-016-9963-5

Article  PubMed  CAS  Google Scholar 

Fogarty MF, Papsun DM, Logan BK (2018) Analysis of fentanyl and 18 novel fentanyl analogs and metabolites by LC–MS–MS, and report of fatalities associated with methoxyacetylfentanyl and cyclopropylfentanyl. J Anal Toxicol 42(9):592–604. https://doi.org/10.1093/jat/bky035

Article  PubMed  CAS  Google Scholar 

Garg A, Solas DW, Takahashi LH, Cassella JV (2010) Forced degradation of fentanyl: identification and analysis of impurities and degradants. J Pharm Biomed Anal 53(3):325–334. https://doi.org/10.1016/j.jpba.2010.04.004

Article  PubMed  CAS  Google Scholar 

Guengerich FP, Yun CH, Macdonald TL (1996) Evidence for a 1-electron oxidation mechanism in N-dealkylation of N,N-dialkylanilines by cytochrome P450 2B1. Kinetic hydrogen isotope effects, linear free energy relationships, comparisons with horseradish peroxidase, and studies with oxygen surrogates. J Biol Chem 271(44):27321–27329. https://doi.org/10.1074/jbc.271.44.27321

Article  PubMed  CAS  Google Scholar 

INCB (2023) Establishing a List of Fentanyl-related Substances, a List of Synthetic Non-fentanyl Opioids and a List for Benzodiazepines and Related New Psychoactive Substances all with no Known Legitimate Uses. https://www.incb.org/incb/en/opioids_project/fentanyl-related-substances-with-no-known-legitimate-use.html

INCB (2024) Reports Published by the International Narcotics Control Board for 2023. https://unis.unvienna.org/unis/en/events/2024/incb_2023.html

Kong L, Walz AJ (2020) Mass spectrometric characterization of carfentanil metabolism in human, dog, and rat lung microsomes via comparison to chemically synthesized metabolite standards. Forensic Toxicol 38(2):352–364. https://doi.org/10.1007/s11419-019-00521-x

Article  CAS  Google Scholar 

Li C, Wu W, Kumar D, Shaik S (2006) Kinetic isotope effect is a sensitive probe of spin state reactivity in C−H hydroxylation of N,N-dimethylaniline by cytochrome P450. J Am Chem Soc 128(2):394–395. https://doi.org/10.1021/ja055987p

Article  PubMed  CAS  Google Scholar 

Li XX, Wang Y, Zheng QC, Zhang HX (2015) Detoxification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by cytochrome P450 enzymes: a theoretical investigation. J Inorg Biochem 154:21–28. https://doi.org/10.1016/j.jinorgbio.2015.10.009

Article  PubMed  CAS  Google Scholar 

Lu T, Chen F (2011) Multiwfn: a multifunctional wavefunction analyzer. J Comput Chem 33(5):580–592. https://doi.org/10.1002/jcc.22885

Article  PubMed  CAS  Google Scholar 

Lu T, Chen F (2012) Quantitative analysis of molecular surface based on improved marching tetrahedra algorithm. J Mol Graph Model 38:314–323. https://doi.org/10.1016/j.jmgm.2012.07.004

Article  PubMed  CAS  Google Scholar 

Luo X, Peng J, Huang K, Liu X, Yang N, Luo Q (2023) Study on electron ionization-mass spectrometry characteristic fragments and cleavage patterns of fentanyl-type new psychoactive substances. Forensic Chem. https://doi.org/10.1016/j.forc.2023.100518

Article  Google Scholar 

Luo X, Chen Q, Huang K, Liu X, Yang N, Luo Q (2025) In vitro metabolism of seven arolyl-derived fentanyl-type new psychoactive substances. Arch Toxicol 99(3):1059–1072. https://doi.org/10.1007/s00204-024-03937-6

Article  PubMed  CAS  Google Scholar 

Meunier B, de Visser SP, Shaik S (2004) Mechanism of oxidation reactions catalyzed by cytochrome P450 enzymes. Chem Rev 104(9):3947–3980. https://doi.org/10.1021/cr020443g

Article  PubMed  CAS  Google Scholar 

Steuer AE, Williner E, Staeheli SN, Kraemer T (2017) Studies on the metabolism of the fentanyl-derived designer drug butyrfentanyl in human in vitro liver preparations and authentic human samples using liquid chromatography-high resolution mass spectrometry (LC-HRMS). Drug Test Anal 9(7):1085–1092. https://doi.org/10.1002/dta.2111

Article  PubMed  CAS  Google Scholar 

UNODC (2022) World Drug Report 2022. https://www.unodc.org/unodc/en/data-and-analysis/world-drug-report-2022.html

UNODC (2023a) Early Warning Advisory on NPS Summary Dashboard. https://www.unodc.org/LSS/Page/NPS/DataVisualisations

UNODC (2023b) World Drug Report 2023: Online Segment. https://www.unodc.org/unodc/en/data-and-analysis/wdr-2023-online-segment.html

Vannoy KJ, Krushinski LE, Dick JE (2024) Capture and detection of aerosolized fentanyl in a suspended electrochemical cell. Anal Chem 96(26):10648–10653. https://doi.org/10.1021/acs.analchem.4c01321

Article  PubMed  PubMed Central  CAS  Google Scholar 

Wade LG (2013) Organic Chemistry, 8th edn. Pearson, Boston, MA

Google Scholar 

WHO (2017) Acetylfentanyl: Critical Review Report. http://www.who.int/medicines/access/controlled-substances/5.2_Acetylfentanyl_CRev.pdf

Xue Z, Zhang Y, Tao J, Kang Y, Chen Z, Xue Y (2016) Theoretical elucidation of the metabolic mechanisms of phenothiazine neuroleptic chlorpromazine catalyzed by cytochrome P450 isoenzyme 1A2. Theor Chem Acc 135(9):218. https://doi.org/10.1007/s00214-016-1943-4

Article  CAS  Google Scholar 

Yamaguchi K, Goda T, Yamaki S, Ohno Y (2015) Structural analysis of quazepam metabolites in bile by ion trap time-of-flight mass spectrometry. Forensic Sci Int 256:7–16. https://doi.org/10.1016/j.forsciint.2015.07.016

Article  PubMed  CAS  Google Scholar 

Comments (0)

No login
gif