TY - JOUR
T1 - Metabolism studies of 4'Cl-CUMYL-PINACA, 4'F-CUMYL-5F-PINACA and 4'F-CUMYL-5F-PICA using human hepatocytes and LC-QTOF-MS analysis
AU - Stalberga, Darta
AU - Ingvarsson, Sarah
AU - Bessa, Ghidaa
AU - Maas, Lisa
AU - Vikingsson, Svante
AU - Persson, Mattias
AU - Norman, Caitlyn
AU - Gréen, Henrik
N1 - Funding Information:
VINNOVA. Grant Number: 2019-03566; Eurostars-2 Joint Programme. Grant Number: E! 113377, NPS-REFORM; European Union's Horizon 2020 Sweden's Innovation Agency Vinnova Strategic Research Area in Forensic Sciences. Grant Number: 2016:7
Copyright:
© 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).
PY - 2023/3
Y1 - 2023/3
N2 - 4'Cl-cumyl-PINACA (SGT-157), 4'F-cumyl-5F-PINACA (4F-cumyl-5F-PINACA, SGT-65) and 4'F-cumyl-5F-PICA (4F-cumyl-5F-PICA, SGT-64) are a series of new halogenated cumyl synthetic cannabinoid receptor agonists (SCRAs). Due to rapid metabolism, monitoring and screening for SCRAs in biological matrices requires identification of their metabolites. It is an essential tool for estimating their spread and fluctuations in the global illicit market. The purpose of this study was to identify human biotransformations of 4'Cl-cumyl-PINACA, 4'F-cumyl-5F-PINACA and 4'F-cumyl-5F-PICA in vitro and characterize for the first time the metabolic pathways of halogenated cumyl SCRAs. 4'Cl-cumyl-PINACA, 4'F-cumyl-5F-PINACA and 4'F-cumyl-5F-PICA were incubated with human hepatocytes in duplicates for 0, 1, 3 and 5 h. The supernatants were analysed in data-dependent acquisition on a UHPLC-QToF-MS, and the potential metabolites were tentatively identified. A total of 11 metabolites were detected for 4'Cl-cumyl-PINACA, 21 for 4'F-cumyl-5F-PINACA and 10 for 4'F-cumyl-5F-PICA. The main biotransformations were oxidative defluorination, followed by hydroxylation with dehydrogenation, N-dealkylation, dihydrodiol formation and glucuronidation. Hydroxylations were most common at the tail moieties with higher abundancy for indole than indazole compounds. N-dealkylations were more common for fluorinated tail chain compounds than the non-fluorinated 4'Cl-cumyl-PINACA. In conclusion, many metabolites retained halogen groups at the cumyl moieties which, in various combinations, may be suitable as analytical biomarkers.
AB - 4'Cl-cumyl-PINACA (SGT-157), 4'F-cumyl-5F-PINACA (4F-cumyl-5F-PINACA, SGT-65) and 4'F-cumyl-5F-PICA (4F-cumyl-5F-PICA, SGT-64) are a series of new halogenated cumyl synthetic cannabinoid receptor agonists (SCRAs). Due to rapid metabolism, monitoring and screening for SCRAs in biological matrices requires identification of their metabolites. It is an essential tool for estimating their spread and fluctuations in the global illicit market. The purpose of this study was to identify human biotransformations of 4'Cl-cumyl-PINACA, 4'F-cumyl-5F-PINACA and 4'F-cumyl-5F-PICA in vitro and characterize for the first time the metabolic pathways of halogenated cumyl SCRAs. 4'Cl-cumyl-PINACA, 4'F-cumyl-5F-PINACA and 4'F-cumyl-5F-PICA were incubated with human hepatocytes in duplicates for 0, 1, 3 and 5 h. The supernatants were analysed in data-dependent acquisition on a UHPLC-QToF-MS, and the potential metabolites were tentatively identified. A total of 11 metabolites were detected for 4'Cl-cumyl-PINACA, 21 for 4'F-cumyl-5F-PINACA and 10 for 4'F-cumyl-5F-PICA. The main biotransformations were oxidative defluorination, followed by hydroxylation with dehydrogenation, N-dealkylation, dihydrodiol formation and glucuronidation. Hydroxylations were most common at the tail moieties with higher abundancy for indole than indazole compounds. N-dealkylations were more common for fluorinated tail chain compounds than the non-fluorinated 4'Cl-cumyl-PINACA. In conclusion, many metabolites retained halogen groups at the cumyl moieties which, in various combinations, may be suitable as analytical biomarkers.
KW - human hepatocytes
KW - metabolism
KW - metabolites
KW - new psychoactive substances
KW - synthetic cannabinoids
UR - http://www.scopus.com/inward/record.url?scp=85145391791&partnerID=8YFLogxK
U2 - 10.1111/bcpt.13829
DO - 10.1111/bcpt.13829
M3 - Article
C2 - 36544361
SN - 1742-7835
VL - 132
SP - 263
EP - 280
JO - Basic & Clinical Pharmacology & Toxicology
JF - Basic & Clinical Pharmacology & Toxicology
IS - 3
ER -