Metabolic patterns of new psychoactive substances: Methyl-ketamine and 2-oxo-PCE in rats using UHPLC-QTOF analysis.

Two structurally similar psychoactive compounds, methyl-ketamine and 2-oxo-PCE, follow different metabolic routes in rats because of a single methyl group. After oral dosing, blood, liver, and urine were analyzed by high-resolution mass spectrometry. Methyl-ketamine mainly underwent N-demethylation and hydroxylation, while 2-oxo-PCE underwent carbonyl hydrogenation and deamination. The methyl group on methyl-ketamine’s aromatic ring blocked a hydrogenation step that occurred in 2-oxo-PCE, instead favoring hydroxylation and dehydration. Human urine samples showed comparable metabolite patterns, confirming the relevance of the rat model. Steric hindrance from small structural differences is a key determinant of how these substances are processed, which helps predict the behavior of related new psychoactive substances.

Study at a glance

Abstract

This study investigated the metabolic profiles of two isomeric psychoactive agents, methyl-ketamine [2-(ortho-tolyl)-2-(methylamino)cyclohexanone] and 2-oxo-PCE [2-(phenyl)-2-(ethylamino)cyclohexanone], in rats. Following oral administration, blood, liver, and urine samples were collected at timed intervals and analyzed via ultrahigh performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). Metabolomic comparisons revealed distinct metabolic pathways driven by structural differences. Methyl-ketamine primarily underwent cyclohexanone hydroxylation, dehydration, N-demethylation, cyclohexanone carbonyl hydrogenation, and glucuronidation, with N-dealkylation as the dominant process. In contrast, 2-oxo-PCE metabolism involved carbonyl hydrogenation of cyclohexanone, N-diethylation, deamination, hydroxylation, dehydration, and glucuronidation. Structural variations-specifically the steric hindrance imposed by the methyl group on o-tolyl in methyl-ketamine-were identified as key factors influencing metabolic divergence. This hindered the carbonyl hydrogenation of cyclohexanone observed in 2-oxo-PCE, while promoting hydroxylation/dehydration reactions in methyl-ketamine. Post-N-dealkylation, methyl-ketamine retained cyclohexyl hydroxylation/dehydration, whereas 2-oxo-PCE exhibited deamination and cyclohexanone carbonyl hydrogenation/dehydration. Notably, urinary metabolite profiles in humans were mirrored those in rats, and relevance was shown. It was elucidated how structural isomerism dictating metabolic outcomes and offering insights into the mechanistic basis of new psychoactive substances. The study underscored steric effects as critical determinants of metabolic pathways and provided a foundation for predicting pharmacokinetic behavior in related compounds.