Chromatography–mass spectrometry studies on the metabolism of synthetic cannabinoids JWH-018 and JWH-073, psychoactive components of smoking mixtures

Grigoryev, Andrej; Savchuk, S. A.; Мельник, А А; Moskaleva, Natalia E.; Dzhurko, Jurij; Ershov, Mihail; Nosyrev, Aleksandr; Vedenin, A. N.; Izotov, Boris N.; Zabirova, Irina; Rozhanets, V. V.

doi:10.1016/j.jchromb.2011.03.034

Cited by 126 publications

(126 citation statements)

References 11 publications

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“…For a final confirmation, the location of the functional group has to be determined. Interestingly, we did not observe N-depentylated metabolites-metabolites that were often observed for other synthetic cannabinoids including JWH-018 (14), JWH-250 (13), AM2201 (18), RCS-4 (10), UR-144 (18), and AB-001 (12). Currently, it is unclear which structural elements favor or prevent N-depentylation as many other structurally similar synthetic cannabinoids including RCS-8 (20), AM-694 (11), AKB-48 (8), XLR-11 (21) and PB-22 and 5F-PB-22 (19) did not undergo Ndepentylation either.…”

Section: In Silico Predictioncontrasting

confidence: 46%

“…Further, it is necessary to identify the most prevalent metabolites for synthesis of reference standards for analytical method development. Since the first appearance of synthetic cannabinoids, many metabolism studies with human liver microsomes (HLM), human hepatocytes, and/or authentic specimens elucidated their metabolic pathways (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

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Pentylindole/Pentylindazole Synthetic Cannabinoids and Their 5-Fluoro Analogs Produce Different Primary Metabolites: Metabolite Profiling for AB-PINACA and 5F-AB-PINACA

Wohlfarth

Castaneto

Zhu

et al. 2015

AAPS J

144

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Abstract. Whereas non-fluoropentylindole/indazole synthetic cannabinoids appear to be metabolized preferably at the pentyl chain though without clear preference for one specific position, their 5-fluoro analogs' major metabolites usually are 5-hydroxypentyl and pentanoic acid metabolites. We determined metabolic stability and metabolites of N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (AB-PINACA) and 5-fluoro-AB-PINACA (5F-AB-PINACA), two new synthetic cannabinoids, and investigated if results were similar. In silico prediction was performed with MetaSite (Molecular Discovery). For metabolic stability, 1 μmol/L of each compound was incubated with human liver microsomes for up to 1 h, and for metabolite profiling, 10 μmol/L was incubated with pooled human hepatocytes for up to 3 h. Also, authentic urine specimens from AB-PINACA cases were hydrolyzed and extracted. All samples were analyzed by liquid chromatography high-resolution mass spectrometry on a TripleTOF 5600+ (AB SCIEX) with gradient elution (0.1% formic acid in water and acetonitrile). High-resolution full-scan mass spectrometry (MS) and information-dependent acquisition MS/MS data were analyzed with MetabolitePilot (AB SCIEX) using different data processing algorithms. Both drugs had intermediate clearance. We identified 23 AB-PINACA metabolites, generated by carboxamide hydrolysis, hydroxylation, ketone formation, carboxylation, epoxide formation with subsequent hydrolysis, or reaction combinations. We identified 18 5F-AB-PINACA metabolites, generated by the same biotransformations and oxidative defluorination producing 5-hydroxypentyl and pentanoic acid metabolites shared with AB-PINACA. Authentic urine specimens documented presence of these metabolites. AB-PINACA and 5F-AB-PINACA produced suggested metabolite patterns. AB-PINACA was predominantly hydrolyzed to AB-PINACA carboxylic acid, carbonyl-AB-PINACA, and hydroxypentyl AB-PINACA, likely in 4-position. The most intense 5F-AB-PINACA metabolites were AB-PINACA pentanoic acid and 5-hydroxypentyl-AB-PINACA.

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Section: In Silico Predictioncontrasting

confidence: 46%

Section: Introductionmentioning

confidence: 99%

Pentylindole/Pentylindazole Synthetic Cannabinoids and Their 5-Fluoro Analogs Produce Different Primary Metabolites: Metabolite Profiling for AB-PINACA and 5F-AB-PINACA

Wohlfarth

Castaneto

Zhu

et al. 2015

AAPS J

144

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“…Analysis of human urine from individuals known to have ingested either JWH-018 or JWH-073 have identified several products of Phase I and II metabolism (Moller et al, 2010;Sobolevsky et al, 2010;Beuck et al, 2011;Grigoryev et al, 2011;Moran et al, 2011;Schneir et al, 2011). 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.…”

Section: Discussionmentioning

confidence: 99%

“…These products are typically vegetative material laced with these potent CB-receptor agonists, and recent clinical data provide evidence of development of anxiety (Schneir et al, 2011), tolerance (Zimmermann et al, 2009), and enhancement of psychoses (Every-Palmer, 2010) in individuals using these products. There is also an evolving body of information available on the metabolism of synthetic cannabinoids, JWH-018 and JWH-073, in body fluids (Moller et al, 2010;Sobolevsky et al, 2010;Beuck et al, 2011;Grigoryev et al, 2011;Moran et al, 2011) and in vitro . Continued characterization of these metabolic pathways is important because recent studies have shown that oxidized products of JWH-018 retain significant in vitro and in vivo activity (L. K. Brents, E. E. Reichard, S. M. Zimmerman, J. H. Moran, W. E. Fantegrossi, and P. L. Prather, unpublished data).…”

Section: Introductionmentioning

confidence: 99%

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

Chimalakonda¹,

Bratton²,

Le³

et al. 2011

Drug Metab Dispos

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ABSTRACT:K2, a synthetic cannabinoid (SC), is an emerging drug of abuse touted as "legal marijuana" and marketed to young teens and first-time drug users. Symptoms associated with K2 use include extreme agitation, syncope, tachycardia, and visual and auditory hallucinations. One major challenge to clinicians is the lack of clinical, pharmacological, and metabolic information for the detection and characterization of K2 and its metabolites in human samples. Information on the metabolic pathway of SCs is very limited. However, previous reports have shown the metabolites of these compounds are excreted primarily as glucuronic acid conjugates. Based on this information, this study evaluates nine human recombinant uridine diphosphate-glucuronosyltransferase (UGT) isoforms and human liver and intestinal microsomes for their ability to glucuronidate hydroxylated metabolites of 1-naphthalenyl-1(1-pentyl-1H-indol-3-yl)-methanone (JWH-018) and (1-butyl-1H-indol-3-yl)-1-naphthalenyl-methanone (JWH-073), the two most common SCs found in K2 products. Conjugates were identified and characterized using liquid chromatography/tandem mass spectrometry, whereas kinetic parameters were quantified using high-performance liquid chromatography-UV-visible methods. UGT1A1, UGT1A3, UGT1A9, UGT1A10, and UGT2B7 were shown to be the major enzymes involved, showing relatively high affinity with K m ranging from 12 to 18 M for some hydroxylated K2s. These UGTs also exhibited a high metabolic capacity for these compounds, which indicates that K2 metabolites may be rapidly glucuronidated and eliminated from the body. Studies of K2 metabolites will help future development and validation of a specific assay for K2 and its metabolites and will allow researchers to fully explore their pharmacological actions.

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“…Of clinical relevance, THC is only a partial agonist of the CB1 receptor, while the SCs are full agonists, meaning that they have no ceiling effect on dose-response relationship and greater potential for overdose and severe toxic effects 24,25 . Some authors suggest that the SC also act on the CB2 receptors located in the peripheral tissues of the immune system, spleen, lymph nodes and tonsils producing immune-modulatory effects 26 .…”

Section: Critical Reviewmentioning

confidence: 99%

Untitled

2013

OA Emergency Medicine

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IntroductionIn recent years, synthetic drugs have been used increasingly by young people on a regular basis and in larger quantities in big music festivals. Some of the synthetic drugs that are popular include "molly" and "spice". These drugs of abuse are on the rise and currently popular among young people and already known for causing health-related complications. The aim of this review was to discuss the drugs of abuse that are on the rise. Conclusion Physicians should be aware of drugrelated symptoms and consider synthetic drug abuse in patients especially those without a history of underlying medical condition, who present with unexplained mental disturbances, seizure, kidney injury, stroke or heart attack and negative urine toxicology.

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Chromatography–mass spectrometry studies on the metabolism of synthetic cannabinoids JWH-018 and JWH-073, psychoactive components of smoking mixtures

Cited by 126 publications

References 11 publications

Pentylindole/Pentylindazole Synthetic Cannabinoids and Their 5-Fluoro Analogs Produce Different Primary Metabolites: Metabolite Profiling for AB-PINACA and 5F-AB-PINACA

Pentylindole/Pentylindazole Synthetic Cannabinoids and Their 5-Fluoro Analogs Produce Different Primary Metabolites: Metabolite Profiling for AB-PINACA and 5F-AB-PINACA

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

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