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In vitro metabolism of the synthetic cannabinoids PX‐1, PX‐2, and PX‐3 by high‐resolution mass spectrometry and their clearance rates in human liver microsomes
Author(s) -
Cooman Travon,
Bell Suzanne
Publication year - 2019
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/rcm.8543
Subject(s) - chemistry , microsome , oxidative deamination , mass spectrometry , orbitrap , metabolism , drug metabolism , metabolite , chromatography , biochemistry , in vitro , enzyme
Rationale N ‐(1‐Amino‐1‐oxo‐3‐phenylpropan‐2‐yl)‐1‐(5‐fluoropentyl)‐1 H ‐indole‐3‐carboxamine (PX‐1), N ‐(1‐amino‐1‐oxo‐3‐phenylpropan‐2‐yl)‐1‐(5‐fluoropentyl)‐1 H ‐indazole‐3‐carboxamide (PX‐2), and N ‐(1‐amino‐1‐oxo‐3‐phenylpropan‐2‐yl)‐1‐(cyclohexylmethyl)‐1 H ‐indazole‐3‐carboxamide (PX‐3) are scheduled synthetic cannabinoids (SCs). Due to the lack of metabolism data and the extensive metabolism of SCs, consumption of these illicit substances is challenging to prove. The aim of this study was to investigate the metabolism of PX‐1, PX‐2, and PX‐3 and propose marker metabolites to confirm their use. Methods PX‐1, PX‐2, and PX‐3 were incubated in pooled human liver microsomes (HLM) to evaluate the phase I metabolites which were identified using a Q‐Exactive hybrid quadrupole‐Orbitrap mass spectrometer. Metabolic stability studies were also performed to investigate the half‐life and clearance rates using an Agilent 6470A triple quadrupole mass spectrometer. Results The calculated half‐lives were 15.1 ± 1.02, 3.4 ± 0.27, and 5.2 ± 0.89 min for PX‐1, PX‐2, and PX‐3, respectively, in HLM. The calculated intrinsic clearance values were 0.046, 0.202, and 0.133 mL/min/mg for PX‐1, PX‐2, and PX‐3, respectively. Four metabolites of PX‐1, six metabolites of PX‐2, and five phase I metabolites of PX‐3 were detected. Oxidative deamination was the common biotransformation between the three compounds and there were no common metabolites. Conclusions The metabolic profiles of PX‐1, PX‐2, and PX‐3 provide valuable information for the detection of their metabolites in forensic samples.