Ketamine-derived designer drug methoxetamine: metabolism including isoenzyme kinetics and toxicological detectability using GC-MS and LC-(HR-)MS n

Abstract

Methoxetamine (MXE; 2-(3-methoxyphenyl)-2-(N-ethylamino)-cyclohexanone), a ketamine analog, is a new designer drug and synthesized for its longer lasting and favorable pharmacological effects over ketamine. The aims of the presented study were to identify the phases I and II metabolites of MXE in rat and human urine by GC-MS and LC-high-resolution (HR)-MS(n) and to evaluate their detectability by GC-MS and LC-MS(n) using authors' standard urine screening approaches (SUSAs). Furthermore, human cytochrome P450 (CYP) enzymes were identified to be involved in the initial metabolic steps of MXE in vitro, and respective enzyme kinetic studies using the metabolite formation and substrate depletion approach were conducted. Finally, human urine samples from forensic cases, where the ingestion of MXE was suspected, were analyzed. Eight metabolites were identified in rat and different human urines allowing postulation of the following metabolic pathways: N-deethylation, O-demethylation, hydroxylation, and combinations as well as glucuronidation or sulfation. The enzyme kinetic studies showed that the initial metabolic step in humans, the N-deethylation, was catalyzed by CYP2B6 and CYP3A4. Both SUSAs using GC-MS or LC-MS(n) allowed monitoring an MXE intake in urine.

Expositions récréatives de 8 patients aux nouvelles drogues de synthèse obtenues sur Internet : à propos de 3,4-méthylènedioxypyrovalérone (MDPV) et de méthoxétamine (MXE)

“…Un seul cas de décès est rapporté dans la littéra-ture avec une concentration de 8,6 mg/L dans le sang fémoral chez un homme de 26 ans décédé au domicile et présentant un oedème pulmonaire [22]. Une étude de métabolisme de la MXE chez la souris confirme la notion de N-déalkylation et de O-déméthylation avec d'autres métabolites hydroxylés et glucuro ou sulfoconjugués également proposés après identification par spectromé-trie en masse tandem et masse exacte [23,24]. Cette étude retrouve également ces métabolites sur nos échantillons urinaires.…”

New Synthetic Drugs in Addictovigilance

“…[60] A recent in vitro study using human hepatic microsomes identified numerous MXE metabolites, also found in the urine of patients presenting acute MXE intoxication. [64,65] The first case reports of the use of this molecule were published at the end of 2011, and they described effects similar to those observed with ketamine, i.e. a dissociative state with detachment of body and mind, leading some users to experiment with imminent death experiences.…”

High-resolution mass spectrometry in toxicology: current status and future perspectives

“…Some of these studies showed that the metabolism of rats was qualitatively comparable to that of humans as the rat metabolites could also be detected in authentic human urine from clinical or forensic case work Welter et al 2013Welter et al , 2015bMeyer et al 2013cMeyer et al , 2015Caspar et al 2015;Helfer et al 2015b;Wink et al 2015c).…”

“…HRMS was applied not only for metabolite identification, but also for quantification of the substrates and/or products in enzyme kinetic studies if very low concentration had to be determined, for example, in cytochrome P450 (CYP) initial activity screenings (Meyer et al 2013c(Meyer et al , 2014dRichter et al 2016;Wink et al 2016), for kinetics of CYPs (Meyer et al 2013aWink et al 2015a), N-acetyl transferases (NAT) (Meyer et al 2014b, e), or esterases (Meyer et al 2014f), or in testing for CYP inhibition by DoA (Dinger et al 2014a, b, 2016a. Cece-Esencan et al…”