Five Postmortem Case Reports with Qualitative Analysis of Cyclopropylfentanyl by LC–MS-MS

Fagiola, Michael; Hahn, Timothy; Avella, Joseph

doi:10.1093/jat/bky094

Cited by 19 publications

(17 citation statements)

References 18 publications

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“…More and more compounds intended to be consumed as substitutes and/or alternatives to classic opioids such as heroin are brought into the drugs of abuse market (Beardsley and Zhang 2018). They are summarized under the term new synthetic opioids (NSO) and have markedly contributed to the dramatic rise in overdose deaths amongst opioid abusers (Fagiola et al 2018;Guerrieri et al 2017;Muller et al 2019;Sharma et al 2019;Solimini et al 2018). This is partly due to their nM affinity at the µ-opioid receptor (MOR) and their enhanced brain penetration owing to higher lipophilicity, but the influence of other toxicodynamic effects cannot be excluded as they were often not characterized prior to abuse (Baumann et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Toxicokinetics and toxicodynamics of the fentanyl homologs cyclopropanoyl-1-benzyl-4´-fluoro-4-anilinopiperidine and furanoyl-1-benzyl-4-anilinopiperidine

et al. 2020

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The two fentanyl homologs cyclopropanoyl-1-benzyl-4´-fluoro-4-anilinopiperidine (4F-Cy-BAP) and furanoyl-1-benzyl-4-anilinopiperidine (Fu-BAP) have recently been seized as new psychoactive substances (NPS) on the drugs of abuse market. As their toxicokinetic and toxicodynamic characteristics are completely unknown, this study focused on elucidating their in vitro metabolic stability in pooled human liver S9 fraction (pHLS9), their qualitative in vitro (pHLS9), and in vivo (zebrafish larvae) metabolism, and their in vitro isozyme mapping using recombinant expressed isoenzymes. Their maximum-tolerated concentration (MTC) in zebrafish larvae was studied from 0.01 to 100 µM. Their µ-opioid receptor (MOR) activity was analyzed in engineered human embryonic kidney (HEK) 293 T cells. In total, seven phase I and one phase II metabolites of 4F-Cy-BAP and 15 phase I and four phase II metabolites of Fu-BAP were tentatively identified by means of liquid chromatography high-resolution tandem mass spectrometry, with the majority detected in zebrafish larvae. N-Dealkylation, N-deacylation, hydroxylation, and N-oxidation were the most abundant metabolic reactions and the corresponding metabolites are expected to be promising analytical targets for toxicological analysis. Isozyme mapping revealed the main involvement of CYP3A4 in the phase I metabolism of 4F-Cy-BAP and in terms of Fu-BAP additionally CYP2D6. Therefore, drug-drug interactions by CYP3A4 inhibition may cause elevated drug levels and unwanted adverse effects. MTC experiments revealed malformations and changes in the behavior of larvae after exposure to 100 µM Fu-BAP. Both substances were only able to produce a weak activation of MOR and although toxic effects based on MOR activation seem unlikely, activity at other receptors cannot be excluded. Keywords In vitro and in vivo metabolism • Metabolic stability • LC-HRMS/MS • Zebrafish larvae • In vitro µ-opioid receptor activity Electronic supplementary material The online version of this article (

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Section: Introductionmentioning

confidence: 99%

Toxicokinetics and toxicodynamics of the fentanyl homologs cyclopropanoyl-1-benzyl-4´-fluoro-4-anilinopiperidine and furanoyl-1-benzyl-4-anilinopiperidine

et al. 2020

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“…Twenty-nine articles were screened at the full text (including articles found using their bibliographies), resulting in 14 articles -nine case reports and five case series. 24,[27][28][29][30][31][32][33][34][35][36][37][38][39] (see Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Causes, Nature and Toxicology of Fentanyl-Analogues Associated Fatalities: A Systematic Review of Case Reports and Case Series

Rauf¹,

Ali²,

Dehele³

et al. 2021

JPR

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Objective: Mortalities due to fentanyl derivatives are on the rise with novel fentanyl analogues and still emerging on the global illicit drug market. They are highly potent and very fatal in low doses, yet there has been a lack of systematic research surrounding this subject. This review aims to assess the causes, nature, and toxicology of fatalities associated with fentanyl analogues. Methods: Five databases: Scopus, Embase, Medline, PubMed and Google Scholar were searched from inception to October 2020 to identify case studies and case series reporting fentanyl analogue-related fatalities. Two independent reviewers screened and selected the articles followed by the data extraction from each article, which included demography, route of administration, causes and nature of death, and the fentanyl analogue implicated. All articles were then subject to quality assessment tools developed by the Joanna Briggs Institute (JBI). A narrative synthesis was undertaken. Results: The initial data search yielded 834 articles, only 14 of which met the inclusion criteria -this included nine case reports and five case series. Of the 1079 fentanyl-analogue related deaths reported, the majority of them occurred in the US (n=1044, 96.8%). The majority of fatalities were male (n=766, 71%), white (n=884, 87%) and in the age ranges 25-34 and 35-44 years (30.5% and 29.6%, respectively). The most common route of administration was intravenous (n=319, 66%) and the manner of death was almost exclusively accidental (99.7%). The predominant cause of death was fentanyl-analogue toxicity (n=292, 85.4%) and involved mixed drug toxicity (n=47, 13.7%). The mean post-mortem fentanyl analogue concentration was 31.6 ng/mL. Conclusion: Most fatalities were reported in the US involving young white males. Overdose through intravenous administration and by mixed drug toxicities with other opioids were the major causes of death. Deaths reported in peer-reviewed literature were relatively less than those reported by real-world data.

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“…Using a method previously described by the author, acetylfentanyl was isolated from case specimens by means of an alkaline liquid/liquid extraction scheme (16). In short, an aliquot of the specimen is mixed with a strong base to convert acetylfentanyl to a nonionized state.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of Acetylfentanyl Following Suspected Heroin Overdose When Complicated by the Presence of Toxic Fentanyl and Alprazolam Concentrations

Fagiola¹,

Hahn²,

Avella³

2019

Academic Forensic Pathology

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A 34-year-old male was reported to be snorting a white powder that was believed to contain heroin. Toxicological analysis revealed free morphine (356 μg/L), fentanyl (34.7 μg/L), alprazolam (64.9 μg/L), and acetylfentanyl (32.9 μg/L) in femoral blood and 6-monoacetylmorphine (6-MAM, <10.0 μg/L) in vitreous fluid. Norfentanyl was only detected in stomach contents (<1.00 μg/total). Heroin, fentanyl, and acetylfentanyl were also detected in solid dose evidence submitted by law enforcement. The fentanyl and alprazolam concentrations might normally be associated with a fatal outcome and are supported with the distribution of fentanyl and alprazolam being consistent with an acute intoxication. In addition, the presence of 6-MAM and a free versus total morphine ratio of 67.9% provide supporting evidence of a rapid death following intranasal (IN) administration. However, the presence of illicit acetylfentanyl complicates toxicologic interpretation due to overlapping recreational and fatal concentrations of this compound reported in the literature as well as a potential for postmortem redistribution (PMR). Reported acetylfentanyl concentrations have also varied when presented with significant fentanyl concentrations and underscore the need to consider a wide range of illicit opioid compounds when investigating drug-related deaths. Based on our comprehensive toxicologic analysis, the results suggest an acute intoxication primarily by IN administration of acetylfentanyl and fentanyl. In addition, we suggest the presence of alprazolam, 6-MAM, and a percentage free morphine is also consistent with rapid death. The cause of death was officially attributed to an acute combined intoxication of acetylfentanyl, fentanyl, alprazolam, and heroin, with the manner of death as accidental.

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Five Postmortem Case Reports with Qualitative Analysis of Cyclopropylfentanyl by LC–MS-MS

Cited by 19 publications

References 18 publications

Toxicokinetics and toxicodynamics of the fentanyl homologs cyclopropanoyl-1-benzyl-4´-fluoro-4-anilinopiperidine and furanoyl-1-benzyl-4-anilinopiperidine

Toxicokinetics and toxicodynamics of the fentanyl homologs cyclopropanoyl-1-benzyl-4´-fluoro-4-anilinopiperidine and furanoyl-1-benzyl-4-anilinopiperidine

Causes, Nature and Toxicology of Fentanyl-Analogues Associated Fatalities: A Systematic Review of Case Reports and Case Series

Evaluation of Acetylfentanyl Following Suspected Heroin Overdose When Complicated by the Presence of Toxic Fentanyl and Alprazolam Concentrations

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