In vitro phase I metabolism of the synthetic cannabimimetic JWH-018

Abstract

A potent synthetic cannabinoid receptor agonist, JHW-018, was recently detected as one of the most prominent active agents in abusively used incenses such as Spice and other herbal blends. The high pharmacological and addictive potency of JWH-018 highlights the importance of elucidating the metabolism of JWH-018, without which a meaningful insight into its pharmacokinetics and its toxicity would not be possible. In the present study, the cytochrome P450 phase I metabolites of JWH-018 were investigated, after in vitro incubation of the drug with human liver microsomes, followed by liquid chromatography-tandem mass spectrometry analysis. This revealed monohydroxylation of the naphthalene ring system, the indole moiety, and the alkyl side chain. In addition, observations were made of dihydroxylation of the naphthalene ring system, and the indole moiety, or as result of a combination of monohydroxylations of both the naphthalene ring system and the indole moiety or the alkyl side chain, or a combination of monohydroxylations of both the indole ring system and the alkyl side chain. There is also evidence of trihydroxylation at different locations of the hydroxyl groups in the molecule. Furthermore, dehydration of the alkyl side chain, in combination with both monohydroxylation and dihydroxylation as well as arene oxidation of the naphthalene ring system, combined with both monohydroxylation and dihydroxylation at different sites of oxidation were found. N-dealkylation also in combination with both monohydroxylation and dihydrodiol formation of the N-dealkylated metabolite was detected. Finally, a metabolite was found carboxylated at the alkyl side chain.

Conjugation of Synthetic Cannabinoids JWH-018 and JWH-073, Metabolites by Human UDP-Glucuronosyltransferases

“…Many of these hydroxylated metabolites have been shown to be monohydroxy derivatives of the naphthalene, indole, or side-chain moieties (Sobolevsky et al, 2010) that are excreted in urine primarily as glucuronic acid conjugates (Sobolevsky et al, 2010;Wintermeyer et al, 2010;Moran et al, 2011), thus implicating the involvement of UGTs in this process.…”

“…Whereas as many as 10 different K2-AAIs are reported to be present in various K2 preparations, the two commonly observed derivatives are JWH-018 and JWH-073 (Vardakou et al, 2010). There are indications that both Phase I and Phase II are involved in the metabolism of these two compounds in vivo (Sobolevsky et al, 2010;Wintermeyer et al, 2010;Moran et al, 2011).…”

High-Resolution Mass Spectrometry for Characterizing the Metabolism of Synthetic Cannabinoid THJ-018 and Its 5-Fluoro Analog THJ-2201 after Incubation in Human Hepatocytes

“…Pentyl chain hydroxylation and further glucuronidation, carboxylation, and naphthalene dihydrodiol formation were detected for both (11,14 ). However, susceptibility to metabolism was different for indole (JWH-018) and indazole (THJ-018) rings.…”

“…However, JWH-018 and AM-2201 metabolism have been intensively studied (12, 14 -16 ). JWH-018 undergoes monohydroxylation on the naphthalene, indole, and pentyl chain, as well as carboxylation (14,15 ). In contrast, AM-2201 primarily undergoes oxidative defluorination and subsequent carboxylation (12,16 ).…”

Application of mass spectrometry to hair analysis for forensic toxicological investigations

“…Nevertheless, several analytical methods were developed to determine some of these new 812 psychoactive substances and/or their metabolites in either blood or urine (Moran et al, 2011;813 Grigoryev et al, 2011;Dresen et al, 2011;Teske et al, 2010;Wintermeyer et al, 2010;Beuck et 814 al., 2011;Kraemer et al, 2009;Sobolevsky, Prasolov, & Rodchenkov, 2010 proposed (Martin et al, 2012). The study reported that 67 real hair samples were analyzed -10 were 822 found positive, with mephedrone concentrations from 0.2 to 313.2 ng/mg; 8 of them were below 6 823 ng/mg.…”