Åstrand A, Töreskog A, Watanabe S et al (2019) Correlations between metabolism and structural elements of the alicyclic fentanyl analogs cyclopropyl fentanyl, cyclobutyl fentanyl, cyclopentyl fentanyl, cyclohexyl fentanyl and 2,2,3,3-tetramethylcyclopropyl fentanyl studied by human hepatocytes and LC-QTOF-MS. Arch Toxicol 93(1):95–106. https://doi.org/10.1007/s00204-018-2330-9

Article  CAS  PubMed  Google Scholar 

Baciocchi E, Bietti M, Gerini MF et al (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  CAS  PubMed  Google Scholar 

Bathelt CM, Ridder L, Mulholland AJ et al (2003) Aromatic hydroxylation by cytochrome P450: model calculations of mechanism and substituent effects. J Am Chem Soc 125(49):15004–15005. https://doi.org/10.1021/ja035590q

Article  CAS  PubMed  Google Scholar 

Bergh MS-S, Bogen IL, Nerem E et al (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 

Bilel S, Murari M, Pesavento S et al (2023) Toxicity and behavioural effects of ocfentanil and 2-furanylfentanyl in zebrafish larvae and mice. Neurotoxicology 95:83–93. https://doi.org/10.1016/j.neuro.2023.01.003

Article  CAS  PubMed  Google Scholar 

Bird HE, Huhn AS, Dunn KE (2023) Fentanyl absorption, distribution, metabolism, and excretion: narrative review and clinical significance related to illicitly manufactured fentanyl. J Addict Med 17(5):503–508. https://doi.org/10.1097/ADM.0000000000001185

Article  PubMed  PubMed Central  Google Scholar 

Brunetti P, Pirani F, Carlier J et al (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  CAS  PubMed  Google Scholar 

Cao J, Ren Q, Chen F et al (2015) Comparative study on the methods for predicting the reactive site of nucleophilic reaction. Sci China:chem 58(12):1845–1852. https://doi.org/10.1007/s11426-015-5494-7

Article  Google Scholar 

Cashman JR, Park SB, Yang ZC et al (1992) Metabolism of nicotine by human liver microsomes: stereoselective formation of trans-nicotine N’-oxide. Chem Res Toxicol 5(5):639–646. https://doi.org/10.1021/tx00029a008

Article  CAS  PubMed  Google Scholar 

Chen H, deGroot MJ, Vermeulen NPE et al (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 Org Chem 62(23):8227–8230. https://doi.org/10.1021/jo9709209

Article  CAS  PubMed  Google Scholar 

de Visser SP, Shaik S (2003) A proton-shuttle mechanism mediated by the porphyrin in benzene hydroxylation by cytochrome P450 enzymes. J Am Chem Soc 125(24):7413–7424. https://doi.org/10.1021/ja034142f

Article  CAS  PubMed  Google Scholar 

Di Trana A, Brunetti P, Giorgetti R et al (2021) In silico prediction, LC-HRMS/MS analysis, and targeted/untargeted data-mining workflow for the profiling of phenylfentanyl in vitro metabolites. Talanta 235:122740. https://doi.org/10.1016/j.talanta.2021.122740

Article  CAS  PubMed  Google Scholar 

EMCDDA (2018) European monitoring centre for drugs and drug addiction. Europol 2017 annual report on the implementation of Council Decision. In. https://op.europa.eu/en/publication-detail/-/publication/aea32ec1-b4aa-11e8-99ee-01aa75ed71a1/language-en Accessed 28 November 2024

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

Article  CAS  PubMed  Google Scholar 

Fu R, Lu T, Chen F (2014) Comparing methods for predicting the reactive site of electrophilic substitution. Wuli Huaxue Xuebao 30(4):628–639. https://doi.org/10.3866/PKU.WHXB201401211

Article  CAS  Google Scholar 

Garg A, Solas DW, Takahashi LH et al (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  CAS  PubMed  Google Scholar 

Goggin MM, Nguyen A, Janis GC (2017) Identification of unique metabolites of the designer opioid furanyl fentanyl. J Anal Toxicol 41(5):367–375. https://doi.org/10.1093/jat/bkx022

Article  CAS  PubMed  Google Scholar 

Groves JT, McClusky GA (1976) Aliphatic hydroxylation via oxygen rebound. Oxygen transfer catalyzed by iron. J Am Chem Soc 98(3):859–861. https://doi.org/10.1021/ja00419a049

Article  CAS  Google Scholar 

Groves JT, McClusky GA, White RE et al (1978) Aliphatic hydroxylation by highly purified liver microsomal cytochrome P-450. Evidence for a carbon radical intermediate. Biochem Biophys Res Commun 81(1):154–160. https://doi.org/10.1016/0006-291X(78)91643-1

Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph Modell 14(1):33–38. https://doi.org/10.1016/0263-7855(96)00018-5

Article  CAS  Google Scholar 

Kanamori T, Iwata YT, Segawa H et al (2018a) Metabolism of fentanyl and acetylfentanyl in human-induced pluripotent stem cell-derived hepatocytes. Biol Pharm Bull 41(1):106–114. https://doi.org/10.1248/bpb.b17-00709

Article  CAS  PubMed  Google Scholar 

Kanamori T, Togawa-Iwata Y, Segawa H et al (2018b) Use of hepatocytes isolated from a liver-humanized mouse for studies on the metabolism of drugs: application to the metabolism of fentanyl and acetylfentanyl. Forensic Toxicol 36(2):467–475. https://doi.org/10.1007/s11419-018-0425-x

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kanamori T, Iwata YT, Segawa H et al (2019) Metabolism of butyrylfentanyl in fresh human hepatocytes: chemical synthesis of authentic metabolite standards for definitive identification. Biol Pharm Bull 42(4):623–630. https://doi.org/10.1248/bpb.b18-00765

Article  CAS  PubMed  Google Scholar 

Kanamori T, Okada Y, Segawa H et al (2021) Detection and confirmation of the ring-opened carboxylic acid metabolite of a new synthetic opioid furanylfentanyl. Forens Toxicol 39(1):114–122. https://doi.org/10.1007/s11419-020-00546-7

Article  CAS  Google Scholar 

Kiraga L, Dzikowski A (2023) Ethical concerns of the veterinarian in relation to experimental animals and in vivo research. Animals 13(15):2476. https://doi.org/10.3390/ani13152476

Article  PubMed  PubMed Central  Google Scholar 

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 et al (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  CAS  PubMed  Google Scholar 

Li XX, Wang Y, Zheng QC et al (2016) 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  CAS  PubMed  Google Scholar 

Lu T, Chen F (2012a) Multiwfn: a multifunctional wavefunction a