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Evidence of enzyme-mediated transesterification of synthetic cannabinoids with ethanol : potential toxicological impact

(2020) FORENSIC TOXICOLOGY. 38(1). p.95-107
Author
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Abstract
Purpose: Synthetic cannabinoids (SCs) represent a large proportion of novel psychoactive substances on the black market and have caused a number of deaths. Polydrug use including combination of SCs and ethanol could further complicate the toxicological impact. To the best of our knowledge, there have been no reports presenting evidence of transesterification between SCs and ethanol in vitro. Methods: The in vitro metabolism of the four carboxylate SCs PB-22, NPB-22, 5-fluoro-PB-22 (5F-PB-22), and 5-fluoro-NPB-22 (5F-NPB-22) in the presence of ethanol using human liver microsomes with and without appropriate enzyme inhibitors was studied. Newly identified SC ethyl esters were chemically synthesised and fully characterised. The activity of these SCs and their ethanol transesterification products were assessed using cannabinoid receptor (CB1 and CB2) activation assays. Results: SCs/ethanol transesterification products were detected and studied using liquid chromatography-high-resolution mass spectrometry. We have shown that the SC ethyl ester formation is mediated by human carboxyl esterase enzymes. The ethyl esters exhibited a reduced activity for the CB receptors compared with their parent compounds. Conclusions: These novel ethyl esters may be useful additional markers of cannabinoid administration, and especially so if they prove to have longer half-lives than their parent compounds.
Keywords
PHARMACOLOGICAL EVALUATION, HUMAN CARBOXYLESTERASES, RECEPTOR AGONISTS, METABOLISM, IDENTIFICATION, COCAETHYLENE, CONSTITUENTS, DEGRADATION, HEADSHOPS, 5F-PB-22, Carboxylate synthetic cannabinoids, In vitro drug metabolism, Transesterification, 5F-NPB-22, Ethanol, Biomarkers

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MLA
Apirakkan, Orapan, et al. “Evidence of Enzyme-Mediated Transesterification of Synthetic Cannabinoids with Ethanol : Potential Toxicological Impact.” FORENSIC TOXICOLOGY, vol. 38, no. 1, 2020, pp. 95–107.
APA
Apirakkan, O., Gavrilovic, I., Floresta, G., Pierre, C., Cannaert, A., Stove, C., … Abbate, V. (2020). Evidence of enzyme-mediated transesterification of synthetic cannabinoids with ethanol : potential toxicological impact. FORENSIC TOXICOLOGY, 38(1), 95–107.
Chicago author-date
Apirakkan, Orapan, Ivana Gavrilovic, Giuseppe Floresta, Cheyanne Pierre, Annelies Cannaert, Christophe Stove, Paul I Dargan, David A Cowan, Lewis Couchman, and Vincenzo Abbate. 2020. “Evidence of Enzyme-Mediated Transesterification of Synthetic Cannabinoids with Ethanol : Potential Toxicological Impact.” FORENSIC TOXICOLOGY 38 (1): 95–107.
Chicago author-date (all authors)
Apirakkan, Orapan, Ivana Gavrilovic, Giuseppe Floresta, Cheyanne Pierre, Annelies Cannaert, Christophe Stove, Paul I Dargan, David A Cowan, Lewis Couchman, and Vincenzo Abbate. 2020. “Evidence of Enzyme-Mediated Transesterification of Synthetic Cannabinoids with Ethanol : Potential Toxicological Impact.” FORENSIC TOXICOLOGY 38 (1): 95–107.
Vancouver
1.
Apirakkan O, Gavrilovic I, Floresta G, Pierre C, Cannaert A, Stove C, et al. Evidence of enzyme-mediated transesterification of synthetic cannabinoids with ethanol : potential toxicological impact. FORENSIC TOXICOLOGY. 2020;38(1):95–107.
IEEE
[1]
O. Apirakkan et al., “Evidence of enzyme-mediated transesterification of synthetic cannabinoids with ethanol : potential toxicological impact,” FORENSIC TOXICOLOGY, vol. 38, no. 1, pp. 95–107, 2020.
@article{8650054,
  abstract     = {{Purpose: Synthetic cannabinoids (SCs) represent a large proportion of novel psychoactive substances on the black market and have caused a number of deaths. Polydrug use including combination of SCs and ethanol could further complicate the toxicological impact. To the best of our knowledge, there have been no reports presenting evidence of transesterification between SCs and ethanol in vitro.
Methods: The in vitro metabolism of the four carboxylate SCs PB-22, NPB-22, 5-fluoro-PB-22 (5F-PB-22), and 5-fluoro-NPB-22 (5F-NPB-22) in the presence of ethanol using human liver microsomes with and without appropriate enzyme inhibitors was studied. Newly identified SC ethyl esters were chemically synthesised and fully characterised. The activity of these SCs and their ethanol transesterification products were assessed using cannabinoid receptor (CB1 and CB2) activation assays.
Results: SCs/ethanol transesterification products were detected and studied using liquid chromatography-high-resolution mass spectrometry. We have shown that the SC ethyl ester formation is mediated by human carboxyl esterase enzymes. The ethyl esters exhibited a reduced activity for the CB receptors compared with their parent compounds.
Conclusions: These novel ethyl esters may be useful additional markers of cannabinoid administration, and especially so if they prove to have longer half-lives than their parent compounds.}},
  author       = {{Apirakkan, Orapan and Gavrilovic, Ivana and Floresta, Giuseppe and Pierre, Cheyanne and Cannaert, Annelies and Stove, Christophe and Dargan, Paul I and Cowan, David A and Couchman, Lewis and Abbate, Vincenzo}},
  issn         = {{1860-8965}},
  journal      = {{FORENSIC TOXICOLOGY}},
  keywords     = {{PHARMACOLOGICAL EVALUATION,HUMAN CARBOXYLESTERASES,RECEPTOR AGONISTS,METABOLISM,IDENTIFICATION,COCAETHYLENE,CONSTITUENTS,DEGRADATION,HEADSHOPS,5F-PB-22,Carboxylate synthetic cannabinoids,In vitro drug metabolism,Transesterification,5F-NPB-22,Ethanol,Biomarkers}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{95--107}},
  title        = {{Evidence of enzyme-mediated transesterification of synthetic cannabinoids with ethanol : potential toxicological impact}},
  url          = {{http://dx.doi.org/10.1007/s11419-019-00491-0}},
  volume       = {{38}},
  year         = {{2020}},
}

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