2. Academic Validation
  3. Systematic In Vitro Metabolic Profiling of the OXIZID Synthetic Cannabinoids BZO-4en-POXIZID, BZO-POXIZID, 5F-BZO-POXIZID, BZO-HEXOXIZID and BZO-CHMOXIZID

Systematic In Vitro Metabolic Profiling of the OXIZID Synthetic Cannabinoids BZO-4en-POXIZID, BZO-POXIZID, 5F-BZO-POXIZID, BZO-HEXOXIZID and BZO-CHMOXIZID

  • J Anal Toxicol. 2023 May 19;47(5):455-463. doi: 10.1093/jat/bkad016.
Shimpei Watanabe 1,  Steven Baginski 2,  Takahiro Iwai 1,  Ritsuko Matsushita 1,  Masahisa Takatsu 1,  Toshio Nakanishi 1,  Karin Lindbom 3,  Craig Mckenzie 2 4,  Svante Vikingsson 3 5,  Robert Kronstrand 3 6,  Henrik Gréen 3 6,  Yasuo Seto 1
Affiliations

Affiliations

  • 1 Forensic Science Group, Photon Science Research Division, RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5148, Japan.
  • 2 Leverhulme Research Centre for Forensic Science, School of Science and Engineering, University of Dundee, Fleming Laboratory, Small's Lane, Dundee DD1 4HN, UK.
  • 3 Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Linköping University, Building 420, Linköping 581 83, Sweden.
  • 4 Chiron AS, Stiklestadveien 1, Trondheim 7041, Norway.
  • 5 Center for Forensic Science, RTI International, 3040 East Cornwallis Rd., Research Triangle Park, NC 27709, USA.
  • 6 Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Artillerigatan 12, Linköping 587 58, Sweden.
PMID: 36857377 DOI: 10.1093/jat/bkad016
Abstract

A new class of synthetic cannabinoids termed OXIZIDs has recently emerged on the recreational drug market. In order to continue the detection of new drugs in biological specimens, the identification of metabolites is essential. The aim of this study was to elucidate the metabolites of BZO-4en-POXIZID produced in human liver microsomes (HLMs) and human hepatocyte incubations and to compare the results with closely related analogs using the same experimental setup. Each drug was incubated for 1 h in HLM and BZO-4en-POXIZID was also incubated in human hepatocytes for up to 3 h. Subsequently, the incubates were analyzed by liquid chromatography-high-resolution mass spectrometry. BZO-4en-POXIZID metabolites were obtained in the incubation with HLMs and human hepatocytes, via the metabolic pathways of dihydrodiol formation, hydroxylation, reduction of the alkene bond and glucuronidation. The major metabolic pathway was found to be dihydrodiol formation at the pentenyl tail moiety. BZO-POXIZID, 5 F-BZO-POXIZID, BZO-HEXOXIZID and BZO-CHMOXIZID underwent similar metabolism to those reported in the literature, via the metabolic pathways of N-dealkylation, hydroxylation, ketone formation and oxidative defluorination (to alcohol or carboxylic acid). The results suggest that OXIZIDs are mainly metabolized at the N-alkyl moiety and the major metabolic pathways are hydroxylation when the N-alkyl moiety is a simple hydrocarbon, whereas functional-group-specific pathways (dihydrodiol formation and oxidative defluorination) are preferred when the moiety contains specific functional groups (alkene or fluoro), as has been observed for other synthetic cannabinoids. The major metabolites generated via these major metabolic pathways should serve as useful analytical targets for urine analysis. Furthermore, the higher abundance of glucuronidated metabolite suggests that enzymatic hydrolysis of glucuronides may be necessary for urine analysis to increase phase I metabolite concentration and improve detection.

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