Dataset Information

Identification and Characterization of Cannabichromene's Major Metabolite Following Incubation with Human Liver Microsomes.

ABSTRACT: Cannabichromene (CBC) is a minor cannabinoid within the array of over 120 cannabinoids identified in the Cannabis sativa plant. While CBC does not comprise a significant portion of whole plant material, it is available to the public in a purified and highly concentrated form. As minor cannabinoids become more popular due to their potential therapeutic properties, it becomes crucial to elucidate their metabolism in humans. Therefore, the goal of this was study to identify the major CBC phase I-oxidized metabolite generated in vitro following incubation with human liver microsomes. The novel metabolite structure was identified as 2'-hydroxycannabicitran using gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. Following the identification, in silico molecular modeling experiments were conducted and predicted 2'-hydroxycannabicitran to fit in the orthosteric site of both the CB₁ and CB₂ receptors. When tested in vitro utilizing a competitive binding assay, the metabolite did not show significant binding to either the CB₁ or CB₂ receptors. Further work necessitates the determination of potential activity of CBC and the here-identified phase I metabolite in other non-cannabinoid receptors.

SUBMITTER: Ward AM

PROVIDER: S-EPMC11206029 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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Identification and Characterization of Cannabichromene's Major Metabolite Following Incubation with Human Liver Microsomes.

Ward Alexandra M AM Shokati Touraj T Klawitter Jost J Klawitter Jelena J Nguyen Vu V Kozell Laura L Abbas Atheir I AI Jones David D Christians Uwe U

Metabolites 20240613 6

Cannabichromene (CBC) is a minor cannabinoid within the array of over 120 cannabinoids identified in the <i>Cannabis sativa</i> plant. While CBC does not comprise a significant portion of whole plant material, it is available to the public in a purified and highly concentrated form. As minor cannabinoids become more popular due to their potential therapeutic properties, it becomes crucial to elucidate their metabolism in humans. Therefore, the goal of this was study to identify the major CBC pha ...[more]

PMID: 38921465

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Project description:CYP-mediated fast metabolism may lead to poor bioavailability, fast drug clearance and significant drug interaction. Thus, metabolic stability screening in human liver microsomes (HLM) followed by metabolic soft-spot identification (MSSID) is routinely conducted in drug discovery. Liver microsomal incubations of testing compounds with fixed single or multiple incubation time(s) and quantitative and qualitative analysis of metabolites using high-resolution mass spectrometry are routinely employed in MSSID assays. The major objective of this study was to develop and validate a simple, effective, and high-throughput assay for determining metabolic soft-spots of testing compounds in liver microsomes using a single variable incubation time and LC/UV/MS. Model compounds (verapamil, dextromethorphan, buspirone, mirtazapine, saquinavir, midazolam, amodiaquine) were incubated at 3 or 5 µM with HLM for a single variable incubation time between 1 and 60 min based on predetermined metabolic stability data. As a result, disappearances of the parents were around 20–40%, and only one or a few primary metabolites were generated as major metabolite(s) without notable formation of secondary metabolites. The unique metabolite profiles generated from the optimal incubation conditions enabled LC/UV to perform direct quantitative estimation for identifying major metabolites. Consequently, structural characterization by LC/MS focused on one or a few major primary metabolite(s) rather than many metabolites including secondary metabolites. Furthermore, generic data-dependent acquisition methods were utilized to enable Q-TOF and Qtrap to continuously record full MS and MS/MS spectral data of major metabolites for post-acquisition data-mining and interpretation. Results from analyzing metabolic soft-spots of the seven model compounds demonstrated that the novel MSSID assay can substantially simplify metabolic soft-spot identification and is well suited for high-throughput analysis in lead optimization.

Dataset Information

Identification and Characterization of Cannabichromene's Major Metabolite Following Incubation with Human Liver Microsomes.

Publications

Identification and Characterization of Cannabichromene's Major Metabolite Following Incubation with Human Liver Microsomes.

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