<i>In vivo</i> and <i>in vitro</i> metabolism of the synthetic cannabinoid JWH‐200

Brabanter, Nik De; Esposito, Simone; Tudela, Eva; Lootens, Leen; Meuleman, Philip; Leroux‐Roels, Geert; Deventer, Koen; Eenoo, Peter Van

doi:10.1002/rcm.6673

Cited by 41 publications

(32 citation statements)

References 25 publications

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“…AOX oxidase functionality was high in humans and monkeys, to a lesser extent in rats, but no activity was apparent in dogs. De Brabanter et al . studied the in vivo metabolism of JWH‐200 in a chimeric mouse model with humanized liver.…”

Section: What Are Synthetic Cannabinoids?mentioning

confidence: 99%

Approaches, Challenges, and Advances in Metabolism of New Synthetic Cannabinoids and Identification of Optimal Urinary Marker Metabolites

Diao

Huestis

2016

Clin Pharma and Therapeutics

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We review approaches for determining metabolism of new synthetic cannabinoids (SCs), and challenges and advances in identifying optimal urinary marker metabolites of SC intake. Metabolic patterns of different SC generations are evaluated, and a practical strategy offered for selecting SC urinary marker metabolites. Novel SCs are incubated with human hepatocytes, the most abundant and characteristic metabolites are identified with high-resolution mass spectrometry, and proposed hepatocyte marker metabolites are confirmed in authentic positive urine samples.

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Section: What Are Synthetic Cannabinoids?mentioning

confidence: 99%

Approaches, Challenges, and Advances in Metabolism of New Synthetic Cannabinoids and Identification of Optimal Urinary Marker Metabolites

Diao

Huestis

2016

Clin Pharma and Therapeutics

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“…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%

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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“…While providing the most reliable data [15], self-administration of drugs is difficult due to possible side effects and ethical concerns and therefore other approaches are commonly taken such as in vitro human hepatocytes [7][8][9][16][17][18][19][20] and human liver microsomes (HLM) [6,14,[21][22][23][24][25][26], and in vivo animals [5,[25][26][27]. The combination of controlled experiments such as human hepatocytes and authentic human urine analysis particularly appears to be valuable [28,29].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Profile of Synthetic Cannabinoids 5F-PB-22, PB-22, XLR-11 and UR-144 by Cunninghamella elegans

Watanabe

Kuzhiumparambil

Nguyen

et al. 2017

AAPS J

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The knowledge of metabolic profile of synthetic cannabinoids is important for the detection of the drugs in urinalysis due to the typical absence or low abundance of parent cannabinoids in human urine. The fungus Cunninghamella elegans has been reported to be a useful tool for metabolism study and thus applicability to synthetic cannabinoids metabolism was examined. In this study, 8-quinolinyl 1-(5-fluoropentyl)-1H-indole-3-carboxylate (5F-PB-22), 8-quinolinyl 1-pentyl-1H-indole-3-carboxylate (PB-22), [1-(5-fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone (XLR-11) and (1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone (UR-144) were incubated with Cunninghamella elegans and the metabolites were identified using liquid chromatographyquadrupole time-of-flight mass spectrometry. The obtained metabolites were compared with reported human metabolites to assess the suitability of the fungus to extrapolate human metabolism. 5F-PB-22 underwent, dihydroxylation, dihydrodiol formation, oxidative defluorination, oxidative defluorination to carboxylic acid, ester hydrolysis and glucosidation, alone and/or in combination. The metabolites of PB-22 were generated by hydroxylation, dihydroxylation, trihydroxylation, dihydrodiol formation, ketone formation, carboxylation, ester hydrolysis and glucosidation, alone and/or in combination. XLR-11 was transformed through hydroxylation, dihydroxylation, aldehyde formation, carboxylation, oxidative defluorination, oxidative defluorination to carboxylic acid and glucosidation, alone and/or in combination. UR-144 was metabolised by hydroxylation, dihydroxylation, trihydroxylation, aldehyde formation, ketone formation, carboxylation, N-dealkylation and combinations. These findings were consistent with previously reported human metabolism except for the small extent of ester hydrolysis observed and absence of glucuronidation. Despite the limitations, Cunninghamella elegans demonstrated the capacity to produce a wide variety of metabolites including some major human metabolites of XLR-11 and UR-144 at high abundance, showing the potential for metabolism of newly emerging synthetic cannabinoids.

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In vivo and in vitro metabolism of the synthetic cannabinoid JWH‐200

Abstract: The metabolite formed by consecutive morpholine cleavage and oxidation of the remaining side chain to a carboxylic group was detected in the highest amounts with the longest detection time. Therefore, it is the best candidate metabolite to detect JWH-200 abuse in urine.

Cited by 41 publications

References 25 publications

Approaches, Challenges, and Advances in Metabolism of New Synthetic Cannabinoids and Identification of Optimal Urinary Marker Metabolites

Approaches, Challenges, and Advances in Metabolism of New Synthetic Cannabinoids and Identification of Optimal Urinary Marker Metabolites

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

Metabolic Profile of Synthetic Cannabinoids 5F-PB-22, PB-22, XLR-11 and UR-144 by Cunninghamella elegans

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