ArticleArchives of toxicology2024
Human metabolism of four synthetic benzimidazole opioids: isotonitazene, metonitazene, etodesnitazene, and metodesnitazene.
Article in Archives of toxicology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 33 citations in OpenAlex.
- Novel 2-Benzylbenzimidazole Opioids: Emerging Drugs of Abuse and Pharmacological Considerations with Nitazene Analogs.Current pain and headache reports · 2026Review
- Genotoxic Potential of Metodesnitazene and Etodesnitazene: Insights with and Without S9 Metabolic Activation.International journal of molecular sciences · 2026Article
- 5-Methyl etodesnitazene human metabolism: LC-ESIAnalytical and bioanalytical chemistry · 2026Article
- Human metabolism and pharmacological profiling of protonitazepyne and metonitazepyne, two highly potent nitazenes: prediction of main metabolite activity based on µ-opioid receptor docking simulations.Archives of toxicology · 2026Article
- Computational design of dynamic biosensors for emerging synthetic opioids.Nature communications · 2026Article
- Article
- The emergence of nitazenes: a new chapter in the synthetic opioid crisis.Archives of toxicology · 2025Review
- Comparison of the Metabolic Profiles Associated with Protonitazene and Protonitazepyne in Two Severe Poisonings.Metabolites · 2025Article
- Dipyanone, a new methadone-like synthetic opioid: In vitro and in vivo human metabolism and pharmacological profiling.Archives of toxicology · 2025Article
- Computational design of dynamic biosensors for emerging synthetic opioids.bioRxiv : the preprint server for biology · 2025Article
- Drug substitutes - Insights on benefits, risks, detection methods, and management strategies: a systematic review.Frontiers in psychiatry · 2025Review
- Biotransformation and kinetics of selected benzimidazole synthetic opioids in human hepatocytes.Frontiers in pharmacology · 2025Article
- Characterization of novel nitazene recreational drugs: Insights into their risk potential from in vitro µ-opioid receptor assays and in vivo behavioral studies in mice.Pharmacological research · 2024Article
- Exploring the Metabolism of Flubrotizolam, a Potent Thieno-Triazolo Diazepine, Using Human Hepatocytes and High-Resolution Mass Spectrometry.Metabolites · 2024Article
- In vitro structure-activity relationships and forensic case series of emerging 2-benzylbenzimidazole 'nitazene' opioids.Archives of toxicology · 2024Article
- Metabolic characterization of the new benzimidazole synthetic opioids - nitazenes.Frontiers in pharmacology · 2024Article
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Authors and funding
9 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Following isotonitazene scheduling in 2019, the availability of alternative 2-benzylbenzimidazole opioids (nitazenes) on the global drug market increased, resulting in many fatalities worldwide. Nitazenes are potent µ-opioid receptor agonists with strong narcotic/analgesic effects, and their concentrations in biological matrices are low, making the detection of metabolite biomarkers of consumption crucial to document use in clinical and forensic settings. However, there is little to no data on the metabolism of the most recently available nitazenes, especially desnitro-analogues. The aim of the research was to assess isotonitazene, metonitazene, etodesnitazene, and metodesnitazene human metabolism and identify specific metabolite biomarkers of consumption. The four analogues were incubated with 10-donor-pooled human hepatocytes, and the incubates were analyzed by liquid chromatography-high-resolution tandem mass spectrometry and data mining with Compound Discoverer (Thermo Scientific); the analysis was supported by in silico metabolite predictions with GLORYx open-access software. Metabolites were identified in postmortem blood and/or urine samples from two metonitazene-positive and three etodesnitazene-positive cases following the same workflow, with and without glucuronide hydrolysis in urine, to confirm in vitro results. Twelve, nine, twenty-two, and ten metabolites were identified for isotonitazene, metonitazene, etodesnitazene, and metodesnitazene, respectively. The main transformations were N-deethylation at the N,N-diethylethanamine side chain, O-dealkylation, and further O-glucuronidation. In vitro and autopsy results were consistent, demonstrating the efficacy of the 10-donor-pooled human hepatocyte model to predict human metabolism. We suggest the parent and the corresponding O-dealkyl- and N-deethyl-O-dealkyl metabolites as biomarkers of exposure in urine after glucuronide hydrolysis, and the corresponding N-deethyl metabolite as additional biomarker in blood.
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