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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.

The quantitative evaluation of the drug mixing condition was conducted for application in the forensic discrimination of drug powders using micro Fourier transform infrared (FT-IR) spectroscopy. Bromhexine hydrochloride (BHCl) and phydroxybenzoic acid (PHBA) were used as the simulated drug and additive, respectively. Equal masses of two chemicals were (1) simply mixed, (2) homogenized using agate mortar, or (3) dissolved in methanol and dried, and then (4) homogenized using agate mortar. The mixed powders dispersed on BaF 2 plates were subjected to mapping analysis of micro FT-IR spectroscopy using synchrotron radiation (SR) or globar light in transmission mode with aperture sizes of 2.5 x 2.5 and 10 x 10μm 2 , and x−y scanning steps of 2.5 and 10 μm, respectively. The areas of the vibration bands specific to BHCl (C−N bending) and PHBA (C�O stretching) were converted to the molar contents (C BHCl , C PHBA ), and the relative content ratio (RCR: C PHBA /[C BHCl + C PHBA ]) was used as one mixing parameter. The resulting two-dimensional distribution map provided the relative spatial localizations of the two species, and frequency histograms with a horizontal axis of RCR were plotted to evaluate the RCR distribution. The percentage frequency of the extreme value in which RCR was 0 or 1 (%EV) was used as one mixing index. After excluding the extreme values, the coefficient of variation (CV) of the RCR distribution was used as another mixing index. The differentiation among four mixing modes could be evaluated from the standpoint of %EV and CV, and the discrimination capacity by SR instrument was superior to that by globe light instrument.

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