Tentative identification of the metabolites of (1‐(cyclohexylmethyl)‐1H‐indol‐3‐yl)‐(2,2,3,3‐tetramethylcyclopropyl)methanone, and the product of its thermal degradation, by in vitro and in vivo methods

Abstract

Synthetic cannabinoids (SCs), mimicking the psychoactive effects of cannabis, consist of a vast array of structurally diverse compounds. A novel compound belonging to the SC family, (1‐(cyclohexylmethyl)‐1H‐indol‐3‐yl)‐(2,2,3,3‐tetramethylcyclopropyl)methanone (named TMCP‐CHM in this article) contains a cyclopropane ring that isomerizes during the smoking process, resulting in a ring‐opened thermal degradant with a terminal double bond in its structure. Metabolites of TMCP‐CHM were tentatively identified in vitro (after incubation of the parent substance with S9 pooled human liver fraction) and in vivo (rat experimental model) studies by accurate‐mass liquid chromatography–tandem mass spectrometry (LC–MS/MS). For the identification of the degradant metabolites, and to study biotransformation of parent substance in the human, urine and hair samples from patients, who had ingested the compound and were subsequently admitted to hospital with drug intoxications, were analyzed. Products of mono‐, di‐, trihydroxylation, carboxylation, and carboxylation combined with hydroxylation of TMCP‐CHM and its degradant were detected in human urine. Metabolism of the degradant included addition of water to the terminal double bond followed by dehydration and formation of a cyclic metabolite. Degradant metabolites prevailed in comparison with metabolites of the parent substance in each metabolite group examined, except carboxylation. N‐Dealkylated metabolites found in human urine originated only from the degradant. Most of the hydroxy metabolites were detected in human urine in both the free form and as glucuronides. The detection of monohydroxylated (M1.1‐M1.3, M/A1.10) and carboxylated/hydroxylated (M4.2, M/A4.3) metabolites of TMCP‐CHM and the hydrated form of the monohydroxylated metabolite of the degradant was found to be convenient for routine analysis.

Air monitoring for illegal drugs including new psychoactive substances: A review of trends, techniques and thermal degradation products

“…Thermal degradants are created as a result of the parent drug being heated, volatilised, or combusted via the relatively common heating/smoking administration route. 28,82,83 The term 'pyrolytic products' specifically refer to products that result from a specific gas-phase thermal degradation reaction which can lead to the initiation of combustion and therefore are referred to differently than thermal degradants. 28 Studies of the thermal breakdown (via smoking or heating) of drug compounds have been conducted since the late 80s where researchers investigated the thermolytic and pyrolytic breakdown of cocaine, heroin and amphetamines to determine how the drug itself may transform.…”

“…LC is typically used in these thermal degradation and pyrolysis studies especially when the researchers are investigating drug trace residues on smoking/heating apparatus (usually in addition to using GC for the smoke/vapour). 27,83,90,94,103,108 There are additional factors that may impact the thermal behaviour of DoA. Gostič et al 89 found that certain mixtures of adulterants with cocaine can impact its thermal behaviour and the extent cocaine can be recovered and detected in its fumes.…”