Metabolic profiling of deschloro‐N‐ethyl‐ketamine and identification of new target metabolites in urine and hair using human liver microsomes and high‐resolution accurate mass spectrometry

Abstract

The aim of this study was to identify new markers of deschloro-N-ethyl-ketamine (O-PCE), a ketamine analogue that has been involved in acute intoxications with severe outcomes including death and whose metabolism has never been studied before. In vitro study after 2-h incubation with pooled human liver microsomes (HLMs) cross-checked by the analysis of urine and hair from a 43-year-old O-PCE user (male) were performed by liquid chromatography-high resolution mass spectrometry (LC-HRMS). Acquired data were processed by the Compound Discoverer® software, and a full metabolic profile of O-PCE was proposed. In total, 15 metabolites were identified, 10 were detected in vitro (HLMs) and confirmed in vivo (urine and/or hair), two were present only in HLMs, and the remaining three metabolites were identified only in biological specimens. While O-PCE was no longer detected in urine, nine metabolites were identified allowing to increase its detection window. In descending order of metabolites abundance, we suggest using 2-en-PCA-N-Glu (34%, first), M3 (16%, second), O-PCA-N-Glu (15.4%, third), OH-O-PCE (15%, fourth) and OH-PCE (11.9%, fifth) as target metabolites to increase the detection window of O-PCE in urine. In hair, nine metabolites were identified. OH-PCA was the major compound (78%) with a relevant metabolite to parent drug ratio (=6) showing its good integration into hair and making it the best marker for long-term monitoring of O-PCE exposure. K E Y W O R D S deschloro-N-ethyl-ketamine, hair, high-resolution mass spectrometry, human liver microsomes, new psychoactive substances 1 | INTRODUCTION Hallucinogens are a diverse group of naturally occurring or synthetic drugs that produce altered perception of reality known as 'Synaesthesia' observed with classic hallucinogens (e.g., LSD, dimethyltryptamine and 5-MeO-DMT), also referred to as 'psychedelics', or a feeling of detachment and dissociation from the self and the environment encountered with dissociative anaesthetics (e.g., ketamine, phencyclidine and methoxetamine). Classic hallucinogens act as serotonin receptor agonists while dissociative anaesthetics possess both stimulant and dissociative properties by inhibiting the reuptake of dopamine, norepinephrine and serotonin, and modulating effects at

Characterization of 3-Hydroxyeticyclidine (3-HO-PCE) Metabolism in Human Liver Microsomes and Biological Samples Using High-Resolution Mass Spectrometry

“…The metabolism of 3-HO-PCE closely resembles that of O-PCE ( N -ethyl-deschloroketamine), which is another designer ketamine analog belonging to the eticyclidine family that we have previously studied [ 16 ].…”

“…According to our previously established procedure [ 16 ], 100 µL of thawed pHLM (20 mg/L) were activated on crushed ice using 250 µL of a 50 µM alamethicin solution mixed with 150 µL of Tris-HCl-MgCl2 buffer solution (pH 7.4). Then, 50 µL of this mixture were combined with 50 µL of a 100 µM 3-HO-PCE solution in MeOH, which had been previously evaporated to dryness under gentle nitrogen stream.…”

“…Detecting metabolites in clinical and forensic settings is a more dependable way of confirming drug intake since the presence of the parent drug alone could be due to external contamination [ 14 , 15 ]. Additionally, metabolites with high abundance and/or a long elimination half-life extend the detection window in biological samples [ 16 ]. Moreover, identification of metabolites is interesting since some of them could also have a pharmacodynamic effect.…”

Arylcyclohexylamine Derivatives: Pharmacokinetic, Pharmacodynamic, Clinical and Forensic Aspects

“…The excretion half-life is approximately 2 to 4 h, and the drug is excreted mainly by the kidneys [ 40 ]. Only 2% of ketamine and norketamine are excreted in unchanged form; the corresponding percentage for dehydronorketamine is about 16% [ 35 , 50 , 65 , 66 , 67 ]. Approximately 80% of hydroxyketamine and hydroxynorketamine are glucuronoconjugated, which facilitates biliary and urinary excretion [ 69 ].…”

Histoire de la kétamine : une molécule ancienne qui a toujours la cote

“…Depuis 2017, certains laboratoires de Toxicologie d'Hong Kong rapportent également l'apparition d'analogues de la kétamine, tels que la deschloro-N-ethylkétamine (2-oxo-PCE) [57]. Cet analogue a été récemment mis en évidence en France [58].…”