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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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

Leong, Huey Sze (author): Univ Technol Sydney, Australia; Univ Sydney, Australia

Watanabe, Shimpei (author): Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Natl Board Forens Med, Deparment Forens Genet & Forens Toxicol, Artillerigatan 12, S-58758 Linkoping, Sweden; RIKEN, Japan

Kuzhiumparambil, Unnikrishnan (author): Univ Technol Sydney, Australia

Fong, Ching Yee (author): Hlth Sci Author, Singapore

Moy, Hooi Yan (author): Hlth Sci Author, Singapore

Yao, Yi Ju (author): Hlth Sci Author, Singapore

Witting, Paul K. (author): Univ Sydney, Australia

Fu, Shanlin (author): Univ Technol Sydney, Australia

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(creator_code:org_t)

2020-12-29
2021
English.
In: Forensic Toxicology. - : SPRINGER. - 1860-8965 .- 1860-8973. ; 39:1, s. 198-212

Related links:: https://liu.diva-por... (primary) (Raw object); show more...; https://link.springe...; https://urn.kb.se/re...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

NATURVETENSKAP -- Kemi -- Analytisk kemi (hsv//swe)
NATURAL SCIENCES -- Chemical Sciences -- Analytical Chemistry (hsv//eng)

Keyword

4F-MDMB-BINACA metabolism; 4F-MDMB-BUTINACA (4F-ADB); HepG2; Cunninghamella elegans; Human liver microsomes; Urinary marker of 4F-MDMB-BINACA intake

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By the author/editor: Leong, Huey Sze; Watanabe, Shimpe ...; Kuzhiumparambil, ...; Fong, Ching Yee; Moy, Hooi Yan; Yao, Yi Ju; show more...; Witting, Paul K.; Fu, Shanlin; show less...

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By the university: Linköping University

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