<i>In vitro</i> phase I metabolism of three phenethylamines 25D‐NBOMe, 25E‐NBOMe and 25N‐NBOMe using microsomal and microbial models

Grafinger, Katharina Elisabeth; Stahl, Katja; Wilke, Andreas; König, S.; Weinmann, Wolfgang

doi:10.1002/dta.2446

Cited by 11 publications

(10 citation statements)

References 39 publications

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“…17 The group of Fu reported the first studies investigating the biotransformation of a chemical class of NPS using C. elegans (strain ATCC 10028b). 21 Our results showed that C. elegans was capable of generating one-third of the metabolites identified in pHLM. 18,19 We previously identified the metabolites of the three phenethylamines (25D-NBOMe, 25E-NBOMe, and 25 N-NBOMe) using pHLM and the fungi C. elegans.…”

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confidence: 58%

“…18,19 We previously identified the metabolites of the three phenethylamines (25D-NBOMe, 25E-NBOMe, and 25 N-NBOMe) using pHLM and the fungi C. elegans. 21 Our results showed that C. elegans was capable of generating one-third of the metabolites identified in pHLM.…”

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confidence: 58%

“…21 The data of the Information independent LC-HR-MS/MS measure- In order to identify potential new metabolites, in silico predictions were performed using Meteor Nexus v.3.0.1 software (Lhasa Limited, Leeds, UK), as described previously.…”

Section: Data Evaluation and Metabolite Identificationmentioning

confidence: 99%

“…In order to identify potential new metabolites, in silico predictions were performed using Meteor Nexus v.3.0.1 software (Lhasa Limited, Leeds, UK), as described previously. 21 The data of the Information independent LC-HR-MS/MS measurements were compared to lists of published metabolites and the results of the in silico predictions, using the Analyst software 1.7.1 TF™ with MasterView™ Software Version 1.1 with the extracted ion current (XIC) tool. The following parameters and cut off values were chosen for data evaluation: a cut-off mass error of 5 ppm, intensities higher than 500 cps and only peaks eluting in the gradient within 2 and 22 minutes.…”

Section: Data Evaluation and Metabolite Identificationmentioning

confidence: 99%

“…Cultivation of C. elegans was performed based on the protocol previously published with minor modifications 21. C. elegans was cultivated in the DSMZ Medium 186 31 containing yeast extract (3 g/L), malt extract (3 g/L), peptone from soy beans (5 g/L) (solution A), and glucose (10 g/L) (solution B).…”

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confidence: 99%

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Investigating the ability of the microbial model Cunninghamella elegans for the metabolism of synthetic tryptamines

Grafinger

Wilke

König

et al. 2018

Drug Testing and Analysis

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Tryptamines can occur naturally in plants, mushrooms, microbes, and amphibians. Synthetic tryptamines are sold as new psychoactive substances (NPS) because of their hallucinogenic effects. When it comes to NPS, metabolism studies are of crucial importance, due to the lack of pharmacological and toxicological data. Different approaches can be taken to study in vitro and in vivo metabolism of xenobiotica. The zygomycete fungus Cunninghamella elegans (C. elegans) can be used as a microbial model for the study of drug metabolism. The current study investigated the biotransformation of four naturally occurring and synthetic tryptamines [N,N-Dimethyltryptamine (DMT), 4-hydroxy-Nmethyl-N-ethyltryptamine (4-HO-MET), N,N-di allyl-5-methoxy tryptamine (5-MeO-DALT) and 5-methoxy-N-methyl-N-isoporpoyltryptamine (5-MeO-MiPT)] in C. elegans after incubation for 72 hours. Metabolites were identified using liquid chromatography-high resolution-tandem mass spectrometry (LC-HR-MS/MS) with a quadrupole time-of-flight (QqTOF) instrument. Results were compared to already published data on these substances. C. elegans was capable of producing all major biotransformation steps: hydroxylation, N-oxide formation, carboxylation, deamination, and demethylation. On average 63% of phase I metabolites found in the literature could also be detected in C. elegans. Additionally, metabolites specific for C. elegans were identified. Therefore, C. elegans is a suitable complementary model to other in vitro or in vivo methods to study the metabolism of naturally occurring or synthetic tryptamines. KEYWORDS fungi Cunninghamella elegans, metabolism, NPS, tryptamines 1 | INTRODUCTIONMetabolism studies are of essential importance in clinical and forensic toxicology, especially when designer drugs or new psychoactive substances (NPS) are the target substrate as very little is known about their pharmacology and toxicology. When a drug of abuse is consumed, the compound is metabolized. General unknown screening analysis should be able to detect metabolites besides parent drugs, the latter which might not even be detectable a few hours after drug consumption. Hence, when developing methods for the detection of a substance of abuse, the main metabolites are used as analytical targets. 1 Therefore, the pharmacological processes and biotransformation of a drug need to be studied. Furthermore, the information about biotransformation of a substance can be used to evaluate its safety and efficacy, because some metabolites have non-negligible psychoactive properties themselves. [2][3][4] Metabolism studies can involve different in vivo and in vitro methods. In vivo methods on humans are difficult to apply because human samples from forensic or clinical cases are rare and human studies raise major ethical concerns (especially in the absence of preclinical safety data). 5 Alternative in vivo methods are animal studies but these are costly and time consuming and require ethical approval.Furthermore, one cannot neglect interspecies differences. In vitro

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confidence: 58%

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confidence: 58%

Section: Data Evaluation and Metabolite Identificationmentioning

confidence: 99%

Section: Data Evaluation and Metabolite Identificationmentioning

confidence: 99%

mentioning

confidence: 99%

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Investigating the ability of the microbial model Cunninghamella elegans for the metabolism of synthetic tryptamines

Grafinger

Wilke

König

et al. 2018

Drug Testing and Analysis

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Severe 25E-NBOH intoxication associated with MDPHP intake: a case report, metabolism study, and literature review

Pelletier,

Gicquel,

Carvelli

et al. 2023

Int J Legal Med

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Monitoring metabolism of synthetic cannabinoid 4F-MDMB-BINACA via high-resolution mass spectrometry assessed in cultured hepatoma cell line, fungus, liver microsomes and confirmed using urine samples

et al. 2020

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Purpose A tert-leucinate derivative synthetic cannabinoid, methyl (2S)-2-([1-(4-fluorobutyl)-1H-indazole-3-carbonyl]amino)-3,3-dimethylbutanoate (4F-MDMB-BINACA, 4F-MDMB-BUTINACA or 4F-ADB) is known to adversely impact health. This study aimed to evaluate the suitability of three different modes of monitoring metabolism: HepG2 liver cells, fungus Cunninghamella elegans (C. elegans) and pooled human liver microsomes (HLM) for comparison with human in-vivo metabolism in identifying suitable urinary marker(s) for 4F-MDMB-BINACA intake. Methods Tentative structure elucidation of in-vitro metabolites was performed on HepG2, C. elegans and HLM using liquid chromatography–tandem mass spectrometry and high-resolution mass spectrometry analysis. In-vivo metabolites obtained from twenty authentic human urine samples were analysed using liquid chromatography–Orbitrap mass spectrometry. Results Incubation with HepG2, C. elegans and HLM yielded nine, twenty-three and seventeen metabolites of 4F-MDMB-BINACA, respectively, formed via ester hydrolysis, hydroxylation, carboxylation, dehydrogenation, oxidative defluorination, carbonylation or reaction combinations. Phase II metabolites of glucosidation and sulfation were also exclusively identified using C. elegans model. Eight in-vivo metabolites tentatively identified were mainly products of ester hydrolysis with or without additional dehydrogenation, N-dealkylation, monohydroxylation and oxidative defluorination with further oxidation to butanoic acid. Metabolites with intact terminal methyl ester moiety, i.e., oxidative defluorination with further oxidation to butanoic acid, were also tentatively identified. Conclusions The in-vitro models presented proved useful in the exhaustive metabolism studies. Despite limitations, HepG2 identified the major 4F-MDMB-BINACA ester hydrolysis metabolite, and C. elegans demonstrated the capacity to produce a wide variety of metabolites. Both C. elegans and HLM produced all the in-vivo metabolites. Ester hydrolysis and ester hydrolysis plus dehydrogenation 4F-MDMB-BINACA metabolites were recommended as urinary markers for 4F-MDMB-BINACA intake.

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In vitro phase I metabolism of three phenethylamines 25D‐NBOMe, 25E‐NBOMe and 25N‐NBOMe using microsomal and microbial models

Cited by 11 publications

References 39 publications

Investigating the ability of the microbial model Cunninghamella elegans for the metabolism of synthetic tryptamines

Investigating the ability of the microbial model Cunninghamella elegans for the metabolism of synthetic tryptamines

Severe 25E-NBOH intoxication associated with MDPHP intake: a case report, metabolism study, and literature review

Monitoring metabolism of synthetic cannabinoid 4F-MDMB-BINACA via high-resolution mass spectrometry assessed in cultured hepatoma cell line, fungus, liver microsomes and confirmed using urine samples

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