Characterization of in vitro metabolites of JWH-018, JWH-073 and their 4-methyl derivatives, markers of the abuse of these synthetic cannabinoids

Gambaro, Veniero; Arnoldi, Sebastiano; S, Bellucci; Casagni, Eleonora; Dell’Acqua, Lucia; Fumagalli, Laura; Pallavicini, Marco; Roda, Gabriella; Rusconi, Chiara; Valoti, Ermanno

doi:10.1016/j.jchromb.2014.03.001

Cited by 20 publications

(5 citation statements)

References 27 publications

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“…BZO-HEXOXIZID, BZO-POXIZID, and ADB-BUPINACA were straightchain hydrocarbon analogues with comparable metabolic patterns. The most abundant metabolites generated in vitro, particularly those resulting from oxidative reactions at the N-alkyl chain, concurred with those for the straight-chain SCs JWH-018, JWH-073, and AB-PINAC and included hydroxylation, dehydrogenation, N-dealkylation, ketone formation, and carboxylation [34,35]. In addition, the 5-fluoro BZO-POXIZID with a fluoropentyl group most frequently had the fluorine atom removed at the 5-position, with a subsequent hydroxylation.…”

Section: Discussionsupporting

confidence: 53%

Study of the Metabolic Profiles of “Indazole-3-Carboxamide” and “Isatin Acyl Hydrazone” (OXIZID) Synthetic Cannabinoids in a Human Liver Microsome Model Using UHPLC-QE Orbitrap MS

et al. 2023

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Unregulated core structures, “isatin acyl hydrazones” (OXIZIDs), have quietly appeared on the market since China legislated to ban seven general core scaffolds of synthetic cannabinoids (SCs). The fast evolution of SCs presents clinical and forensic toxicologists with challenges. Due to extensive metabolism, the parent compounds are barely detectable in urine. Therefore, studies on the metabolism of SCs are essential to facilitate their detection in biological matrices. The aim of the present study was to elucidate the metabolism of two cores, “indazole-3-carboxamide” (e.g., ADB-BUTINACA) and “isatin acyl hydrazone” (e.g., BZO-HEXOXIZID). The in vitro phase I and phase II metabolism of these six SCs was investigated by incubating 10 mg/mL pooled human liver microsomes with co-substrates for 3 h at 37 °C, and then analyzing the reaction mixture using ultrahigh-performance liquid chromatography-quadrupole/electrostatic field orbitrap mass spectrometry. In total, 9 to 34 metabolites were detected for each SC, and the major biotransformations were hydroxylation, dihydrodiol formation (MDMB-4en-PINACA and BZO-4en-POXIZID), oxidative defluorination (5-fluoro BZO-POXIZID), hydrogenation, hydrolysis, dehydrogenation, oxidate transformation to ketone and carboxylate, N-dealkylation, and glucuronidation. Comparing our results with previous studies, the parent drugs and SC metabolites formed via hydrogenation, carboxylation, ketone formation, and oxidative defluorination were identified as suitable biomarkers.

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Section: Discussionsupporting

confidence: 53%

Study of the Metabolic Profiles of “Indazole-3-Carboxamide” and “Isatin Acyl Hydrazone” (OXIZID) Synthetic Cannabinoids in a Human Liver Microsome Model Using UHPLC-QE Orbitrap MS

et al. 2023

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“…Furthermore, hydroxylation’s take place on the aliphatic chain, the indole, the naphthalene, or the substituted aromatic rings that can be secondarily metabolized to carboxylic acids then conjugated to glucuronic acid. 108 , 109 CYP3A4 has been recently demonstrated to be the major CYP enzyme responsible for the oxidative metabolism of AKB-48. 110 Ashino et al suggested that SCs, especially naphthoylindole derivatives, are capable of inhibiting CYP1A enzymatic activity as do the major metabolites present in marijuana, cannabinol and cannabidiol.…”

Section: Availability and Usage Demographicsmentioning

confidence: 99%

Emerging drugs of abuse: current perspectives on synthetic cannabinoids

Debruyne¹,

Boisselier²

2015

SAR

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New psychoactive drugs that have appeared over the last decade are typically dominated by cathinones and synthetic cannabinoids (SCs). SCs have been emerging as recreational drugs because they mimic the euphoria effect of cannabis while still being legal. Sprayed on natural herb mixtures, SCs have been primarily sold as “herbal smoking blends” or “herbal incense” under brand names like “Spice” or “K2”. Currently, SCs pure compounds are available from websites for the combination with herbal materials or for the use in e-cigarettes. For the past 5 years, an ever increasing number of compounds, representative of different chemical classes, have been promoted and now represent a large assortment of new popular drugs of abuse, which are difficult to properly identify. Their legal status varies by country with many government institutions currently pushing for their control. The in vitro binding to CB1/CB2 receptors is usually well-known and considerable differences have been found in the CB1 versus CB2 selectivity and potency within the different SCs, with several structure-activity relations being evident. Desired effects by CB1 agonist users are relaxation/recreative, however, cardiovascular, gastrointestinal, or psychiatric/neurological side effects are commonly reported. At present there is no specific antidote existing if an overdose of designer drugs was to occur, and no curative treatment has been approved by health authorities. Management of acute toxic effects is mainly symptomatic and extrapolated from experience with cannabis.

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“…The metabolism studies of SCs are based on in vivo experiments [40,[43][44][45][46][47][48][49][50][51][52][53] or on in vitro experiments with human or rat liver microsomes [24,41,43,44,[53][54][55][56][57][58][59][60][61][62][63]. Due to the speed of both the emergence and spread of SCs on the world market, the pharmacokinetics properties of some SCs have not been satisfactorily investigated.…”

Section: Pharmacological and Toxicological Aspects Of Synthetic Cannamentioning

confidence: 99%

Bioanalytical methods for the determination of synthetic cannabinoids and metabolites in biological specimens

Aldlgan

Torrance

2016

TrAC Trends in Analytical Chemistry

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Recently the use of synthetic cannabinoids (SCs) has increased around the world. As a result, the importance for accurate analysis of SCs in human biological matrices is evident and continues to be especially challenging due to their chemical structures being constantly modified. Many methods have been published recently for the analysis of SCs in human biological samples. This review provides an overview of the analytical methods used for the analysis of SCs and their metabolites in biological specimens with a special focus on chromatographic analysis and sample preparation.Liquid chromatography assay is the most commonly used for confirmation purposes of SCs and their metabolites in biological matrices. In blood and oral fluid, analysis of SCs must be very sensitive. In urine, SCs have extensive metabolism pathways; therefore the main target compounds are their hydroxyl and carboxyl metabolites, which is important to recognise when establishing clinical and forensic toxicology analytical methods.

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Characterization of in vitro metabolites of JWH-018, JWH-073 and their 4-methyl derivatives, markers of the abuse of these synthetic cannabinoids

Cited by 20 publications

References 27 publications

Study of the Metabolic Profiles of “Indazole-3-Carboxamide” and “Isatin Acyl Hydrazone” (OXIZID) Synthetic Cannabinoids in a Human Liver Microsome Model Using UHPLC-QE Orbitrap MS

Study of the Metabolic Profiles of “Indazole-3-Carboxamide” and “Isatin Acyl Hydrazone” (OXIZID) Synthetic Cannabinoids in a Human Liver Microsome Model Using UHPLC-QE Orbitrap MS

Emerging drugs of abuse: current perspectives on synthetic cannabinoids

Bioanalytical methods for the determination of synthetic cannabinoids and metabolites in biological specimens

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