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

Diao, Xingxing; Huestis, Marilyn A.

doi:10.1002/cpt.534

Cited by 91 publications

(90 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Ideally, a confirmation of our results with urine specimens from authentic cases of ADB-CHMINACA intake would be advantageous (33); however, despite our efforts, we were unable to obtain such specimens. It is noteworthy that structural analogs AB-CHMINACA (24) and MDMB-CHMICA (25,35) in vivo metabolism corroborates our results: the most intense urinary metabolites are monohydroxylated at the cyclohexylmethyl tail, as observed in ADB-CHMINACA hepatocyte incubations.…”

Section: Comparison To Reference Standardsmentioning

confidence: 93%

“…Human hepatocyte profiles generally match better with authentic urine SC metabolites because they are functioning complete cells and contain comprehensive phase I and II metabolic enzymes and cofactors, uptake and efflux transporters, and drug binding proteins (29-32). Therefore, we incubated ADB-CHMINACAwith human hepatocytes and identified metabolites with liquid chromatography-high resolution tandem mass spectrometry (LC-HRMS/MS), following our previously recommended workflow (33). Additionally, we compared our results to commercially available reference standards of theoretical ADB-CHMINACA metabolites.…”

Section: Adb-chminaca (N-[1′-(aminocarbonyl)-2′2′mentioning

confidence: 99%

See 1 more Smart Citation

Identification of New Synthetic Cannabinoid ADB-CHMINACA (MAB-CHMINACA) Metabolites in Human Hepatocytes

Carlier

Diao

Sempio

et al. 2017

AAPS J

View full text Add to dashboard Cite

Abstract.ADB-CHMINACA (MAB-CHMINACA) is a new synthetic cannabinoid with high potency and many reported adverse events and fatalities. The drug is currently scheduled in several countries in Europe and the USA. Analytical methods need to be developed to confirm ADB-CHMINACA intake for clinical and forensic programs. For many synthetic cannabinoids, parent compound is not detectable in biological samples after intake, making the detection of metabolites the only way to prove consumption. Therefore, detection of ADB-CHMINACA metabolites in biological specimens is critical. Since there are currently no published data on ADB-CHMINACA metabolism, we aimed to identify its major metabolites. Cryopreserved human hepatocytes were incubated with 10 μmol/L ADB-CHMINACA for 3 h. Incubations were analyzed with liquid chromatography on a biphenyl column, high resolution tandem mass spectrometry (orbitrap), and metabolite identification software. A reference standard of six commercially available potential metabolites was simultaneously analyzed under the same conditions to allow correct assignment of isomers. We detected ten major metabolites. Biotransformations mainly occurred at the cyclohexylmethyl tail of the compound, as also observed with structural analogs' metabolism. Minor reactions also occurred at the tert-butyl chain. Only two analytical standards of potential metabolites matched an actual metabolite detected in hepatocyte incubations. We recommend A9 (ADB-CHMINACA hydroxycyclohexylmethyl), A4 (ADB-CHMINACA 4″-hydroxycyclohexyl), and A6 (ADB-CHMINACA hydroxycyclohexylmethyl) as metabolite targets to document ADB-CHMINACA intake in clinical and forensic cases. Additionally, these results will guide analytical standard manufacturers to better provide suitable references for further studies on ADB-CHMINACA metabolism.

show abstract

Section: Comparison To Reference Standardsmentioning

confidence: 93%

Section: Adb-chminaca (N-[1′-(aminocarbonyl)-2′2′mentioning

confidence: 99%

Identification of New Synthetic Cannabinoid ADB-CHMINACA (MAB-CHMINACA) Metabolites in Human Hepatocytes

Carlier

Diao

Sempio

et al. 2017

AAPS J

View full text Add to dashboard Cite

show abstract

“…[1][2][3][4] SCs and some of their metabolites mimic the effects of Δ 9 -tetrahydrocannabinol (the major psychoactive component found in cannabis) by a high affinity interaction with the cannabinoid type 1 (CB1) and type 2 (CB2) receptors. 5,7,8,[10][11][12] The SC 5Cl-THJ-018 [(1-(5-chloropentyl)-1H-indazol-3-yl) (naphthalen-1-yl)methanone] is a new SC with a napthoylindazole structure, derived from THJ-018 by addition of a chlorine on the pentyl side chain. 4,9 As most investigated SCs are prone to extensive biotransformation, parent compounds are rarely detected in urine.…”

Section: Introductionmentioning

confidence: 99%

Suspect and non‐target screening workflows to investigate the in vitro and in vivo metabolism of the synthetic cannabinoid 5Cl‐THJ‐018

Vervliet

Mortelé

Gys

et al. 2018

Drug Testing and Analysis

View full text Add to dashboard Cite

The use of synthetic cannabinoids causes similar effects as Δ 9 -tetrahydrocannabinol and long-term (ab)use can lead to health hazards and fatal intoxications. As most investigated synthetic cannabinoids undergo extensive biotransformation, almost no parent compound can be detected in urine, which hampers forensic investigations.Limited information about the biotransformation products of new synthetic cannabinoids makes the detection of these drugs in various biological matrices challenging.This study aimed to identify the main in vitro biotransformation pathways of 5Cl-THJ-018 and to compare these findings with an authentic urine sample of a 5Cl-THJ-018 user. The synthetic cannabinoid was incubated with pooled human liver microsomes and cytosol to simulate phase I and phase II biotransformations. Resulting extracts were analyzed with liquid chromatography coupled to quadrupole time-offlight mass spectrometry (LC-QTOF-MS). Three different data analysis workflows were applied to identify biotransformation products. A suspect screening workflow used an in-house database built from literature data and in silico biotransformation predictions. Two non-target screening workflows used a commercially available software and an open-source software for mass spectrometry data processing. A total of 23 in vitro biotransformation products were identified, with hydroxylation, oxidative dechlorination, and dihydrodiol formation pathways as the main phase I reactions.Additionally, five glucuronidated and three sulfated phase II conjugates were identified. The predominant in vivo pathway was through oxidative dechlorination and in total six metabolites of 5Cl-THJ-018 were identified. Biotransformation products both in vitro and in vivo were successfully identified using complementary suspect and non-target screening workflows. KEYWORDS cytosolic fractions, human liver microsomes, In vitro biotransformation, liquid chromatographymass spectrometry, new psychoactive substances Philippe Vervliet and Olivier Mortelé joint first authors.

show abstract

“…Furthermore, quantity of metabolites obtained is usually not sufficient for isolation [30], limiting the analysis to the use of mass spectrometry. However, unambiguous structural elucidation may not be possible without techniques such as nuclear magnetic resonance (NMR) spectroscopy [29].…”

Section: Introductionmentioning

confidence: 99%

“…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]. However, cost, maintenance, species differences and/or ethics can be an issue with these models [30].…”

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

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 91 publications

References 65 publications

Identification of New Synthetic Cannabinoid ADB-CHMINACA (MAB-CHMINACA) Metabolites in Human Hepatocytes

Identification of New Synthetic Cannabinoid ADB-CHMINACA (MAB-CHMINACA) Metabolites in Human Hepatocytes

Suspect and non‐target screening workflows to investigate the in vitro and in vivo metabolism of the synthetic cannabinoid 5Cl‐THJ‐018

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

Contact Info

Product

Resources

About