Cytochrome P450-Mediated Oxidative Metabolism of Abused Synthetic Cannabinoids Found in K2/Spice: Identification of Novel Cannabinoid Receptor Ligands

Chimalakonda, Krishna C.; Seely, Kathryn A.; Bratton, Stacie M.; Brents, Lisa K.; Moran, Cindy L.; Endres, Gregory W.; James, Laura P.; Hollenberg, Paul F.; Prather, Paul L.; Radominska‐Pandya, Anna; Moran, Jeffery H.

doi:10.1124/dmd.112.047530

Cited by 172 publications

(231 citation statements)

References 49 publications

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“…We propose M9 as 4Ј-OH-THJ-018 because -hydroxylation and -1-hydroxylation were usually the primary biotransformations for drugs with aliphatic side chains and displayed similar physicochemical properties (22)(23)(24). This phenomenon also was observed for 5Ј-OH-JWH-018 and 4Ј-OH-JWH-018 (11 ). Glucuronidation of M9 forms M3 (4Ј-OH-THJ-018 glucuronide) (Fig.…”

Section: '-Hydroxylation and Further Oxidation And Glucuronidationsupporting

confidence: 65%

“…Likewise, no indazole-hydroxylated metabolites were observed for AKB-48 and AB-PINACA (19,34 ). Both AM-2201 and THJ-2201 underwent oxidative defluorination with subsequent carboxylation and glucuronidation (11,16 ). Surprisingly, an uncommon pathway was observed for THJ-2201, i.e., glucuronidation after N-oxidation (F16).…”

Section: Thj-018 and Thj-2201 Metabolism Compared With Jwh-018 And Ammentioning

confidence: 98%

“…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.…”

Section: Thj-018 and Thj-2201 Metabolism Compared With Jwh-018 And Ammentioning

confidence: 99%

“…they should possess similar affinity to cannabinoid receptors as JWH-018 and AM-2201 (11 ). Adverse reactions, such as kidney pains, muscle spasms, and paranoia, were reported on drug-user forums (9 ).…”

mentioning

confidence: 99%

“…All investigated SCs undergo extensive metabolism in humans, with little to no parent compound excreted in urine (11)(12)(13), complicating detection, since metabolites are initially unknown. Because urine is the most common matrix in clinical, antidoping, and military drug testing, characterizing THJ-018 and THJ-2201 metabolism is essential for developing effective urine screening methods.…”

mentioning

confidence: 99%

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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

Diao

Wohlfarth

Pang³

et al. 2016

Clinical Chemistry

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BACKGROUND Despite increasing prevalence of novel psychoactive substances, no human metabolism data are currently available, complicating laboratory documentation of intake in urine samples and assessment of the drugs' pharmacodynamic, pharmacokinetic, and toxicological properties. In 2014, THJ-018 and THJ-2201, synthetic cannabinoid indazole analogs of JWH-018 and AM-2201, were identified, with the National Forensic Laboratory Information System containing 220 THJ-2201 reports. Because of numerous adverse events, the Drug Enforcement Administration listed THJ-2201 as Schedule I in January 2015. METHODS We used high-resolution mass spectrometry (HR-MS) (TripleTOF 5600+) to identify optimal metabolite markers after incubating 10 μmol/L THJ-018 and THJ-2201 in human hepatocytes for 3 h. Data were acquired via full scan and information-dependent acquisition triggered product ion scans with mass defect filter. In silico metabolite predictions were performed with MetaSite and compared with metabolites identified in human hepatocytes. RESULTS Thirteen THJ-018 metabolites were detected, with the major metabolic pathways being hydroxylation on the N-pentyl chain and further oxidation or glucuronidation. For THJ-2201, 27 metabolites were observed, predominantly oxidative defluorination plus subsequent carboxylation or glucuronidation, and glucuronidation of hydroxylated metabolites. Dihydrodiol formation on the naphthalene moiety was observed for both compounds. MetaSite prediction matched well with THJ-018 hepatocyte metabolites but underestimated THJ-2201 oxidative defluorination. CONCLUSIONS With HR-MS for data acquisition and processing, we characterized THJ-018 and THJ-2201 metabolism in human hepatocytes and suggest appropriate markers for laboratories to identify THJ-018 and THJ-2201 intake and link observed adverse events to these new synthetic cannabinoids.

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Section: '-Hydroxylation and Further Oxidation And Glucuronidationsupporting

confidence: 65%

Section: Thj-018 and Thj-2201 Metabolism Compared With Jwh-018 And Ammentioning

confidence: 98%

Section: Thj-018 and Thj-2201 Metabolism Compared With Jwh-018 And Ammentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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

Diao

Wohlfarth

Pang³

et al. 2016

Clinical Chemistry

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Chiral Separation by LC

Barreiro

Cass

2023

Chiral Separations and Stereochemical Elucidation

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UPLC‐HR‐MS/MS‐based determination study on the metabolism of four synthetic cannabinoids, ADB‐FUBICA, AB‐FUBICA, AB‐BICA and ADB‐BICA, by human liver microsomes

Liu

et al. 2017

Biomedical Chromatography

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Since 2012, several cannabimimetic indazole and indole derivatives with valine amino acid amide residue have emerged in the illicit drug market, and have gradually replaced the old generations of synthetic cannabinoids (SCs) with naphthyl or adamantine groups. Among them, ADB-FUBICA [N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indole-3-carboxamide], AB-FUBICA [N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indole-3-carboxamide], AB-BICA [N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-benzyl-1H-indole-3-carboxamide] and ADB-BICA [N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-benzyl-1H-indole-3-carboxamide] were detected in China recently, but unfortunately no information about their in vitro human metabolism is available. Therefore, biomonitoring studies to screen their consumption lack any information about the potential biomarkers (e.g. metabolites) to target. To bridge this gap, we investigated their phase I metabolism by incubating with human liver microsomes, and the metabolites were identified by ultra-performance liquid chromatography-high resolution-tandem mass spectrometry. Metabolites generated by N-dealkylation and hydroxylation on the 1-amino-alkyl moiety were found to be predominant for all these four substances, and others which underwent hydroxylation, amide hydrolysis and dehydrogenation were also observed in our investigation. Based on our research, we recommend that the N-dealkylation and hydroxylation metabolites are suitable and appropriate analytical markers for monitoring their intake.

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Cytochrome P450-Mediated Oxidative Metabolism of Abused Synthetic Cannabinoids Found in K2/Spice: Identification of Novel Cannabinoid Receptor Ligands

Cited by 172 publications

References 49 publications

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

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

Chiral Separation by LC

UPLC‐HR‐MS/MS‐based determination study on the metabolism of four synthetic cannabinoids, ADB‐FUBICA, AB‐FUBICA, AB‐BICA and ADB‐BICA, by human liver microsomes

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