SystematicIn VitroMetabolic Profiling of the OXIZID Synthetic Cannabinoids BZO-4en-POXIZID, BZO-POXIZID, 5F-BZO-POXIZID, BZO-HEXOXIZID and BZO-CHMOXIZID

Abstract

The new class of synthetic cannabinoids termed OXIZIDs has recently emerged on the recreational drug market. In order to continue detection of new drugs in biological specimens, identification of metabolites is essential. The aim of this study was to elucidate the metabolites of BZO-4en-POXIZID produced in human liver microsomes (HLM) 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 HLM 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, 5F-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 in urine analysis to increase phase I metabolite concentration and improve detection.

Metabolism of ADB‐FUBIATA in zebrafish and pooled human liver microsomes investigated by liquid chromatography–high‐resolution mass spectrometry

“…The use of both zebrafish and pHLM metabolic models may provide a more comprehensive and accurate simulation of the metabolic pathway of ADB-FUBIATA in the human body. M1, M2, M4, M5, and M8 were also found in another study, 21 and M3, M6, M7, and M9-M18 were not mentioned, which may be due to the different HLM donors.…”

“…17 Nine metabolites of ADB-FUBIATA were observed in a study involving human liver microsomes (HLMs). 21 However, little is known about the in vivo metabolism of ADB-FUBIATA.…”

“…ADB‐FUBIATA showed high agonistic potency at CB1 receptors, with a maximal receptor activation of 141%, exceeding that of CP55,940 17 . Nine metabolites of ADB‐FUBIATA were observed in a study involving human liver microsomes (HLMs) 21 . However, little is known about the in vivo metabolism of ADB‐FUBIATA.…”

“…The biotransformation is dominated by hydroxylation, Ndealkylation, hydrolysis of amides, and dehydrogenation and F I G U R E 2 Postulated metabolic pathways of ADB-FUBIATA subsequent glucuronidation. Hydroxylation and N-dealkylation are common metabolic reactions in indole carboxamide SCs, such as AFUBIATA, CH-FUBIATA, and CH-PIATA 21. The hydroxylated metabolites (M1/M2) can be recommended as metabolic markers for ADB-FUBIATA, because of the structural characteristics and high intensity.…”

Changing trends in novel benzodiazepine use within Scottish prisons: detection, quantitation, prevalence, and modes of use

“…Changes in international legislation can greatly impact the prevalence of compounds available on the NPS market, both locally and globally. [57][58][59] The evolution of the benzodiazepine-type drugs however, it should also be noted that the number of samples submitted for testing has greatly decreased over the study period.…”