Study of metabolism and potential toxicity of nine synthetic opioid analogs using the zebrafish larvae model

Author:

Murari Matilde1,Pesavento Sara1,Greco Francesca2,Vettori Andrea2,Tagliaro Franco1,Gottardo Rossella1ORCID

Affiliation:

1. Unit of Forensic Medicine, Department of Diagnostics and Public Health University of Verona Verona Italy

2. Department of Biotechnology University of Verona Verona Italy

Abstract

AbstractThe use of novel psychoactive substances (NPSs) has dramatically increased worldwide, and among them, synthetic opioids are one of the fastest growing groups, where cinnamylpiperazines and 2‐benzylbenzimidazoles represent two of the most relevant subclasses. However, the data on their toxicity and metabolism are still limited. The aim of the present study was to evaluate the toxicity and metabolic pathways of some compounds belonging to these families, namely, AP‐237, 2‐methyl AP‐237, isotonitazene, flunitazene, etodesnitazene, metonitazene, metodesnitazene, N‐pyrrolidino etonitazene, and butonitazene. The study was performed using a zebrafish early life stages model. In fact, zebrafish (Danio rerio) embryos and larvae have recently been recognized as a suitable animal model in alternative to mammals, because they require less time and resources and do not need complex procedures for ethics approval. The cellular toxicity after a single administration was assessed at the fourth day post‐fertilization with acridine orange staining. Possible morphological defects were evaluated with a light microscope after 24 h of exposure to 1 μmol/L concentration of each drug. Subsequently, the larvae were euthanized and underwent analysis of drug metabolites using UPLC coupled to an Orbitrap high‐resolution mass spectrometer. High rates of morphological defects, as well as of cellular death, were detected, but no significant difference in mortality between treatment and control groups was observed. In addition, several metabolites, mainly produced through monohydroxylation, N‐dealkylation, and O‐dealkylation, were identified in the larvae extracts.

Publisher

Wiley

Subject

Spectroscopy,Pharmaceutical Science,Environmental Chemistry,Analytical Chemistry

Reference34 articles.

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3. United Nations Office on Drugs and Crime (UNODC).UNODC Early Warning Advisory (EWA) on New Psychoactive Substances (NPS).2020.https://www.unodc.org/LSS/Home/NPS

4. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).EMCDDA initial report on the new psychoactive substance N N‐diethyl‐2‐[[4‐(1‐methylethoxy)phenyl]methyl]‐5‐nitro‐ 1H‐benzimidazole‐1‐ethanamine (isotonitazene).2020. doi:10.1093/tandt/ttm111

5. World Health Organisation.Critical review report: isotonitazene.2020.

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