Keywords

metabolites, synthetic cannabinoids, metabolism, in vitro

Abstract

Synthetic cannabinoids (SCs) have emerged as a complex and evolving class of compounds designed to mimic the effects of natural cannabinoids, targeting the endocannabinoid system. Despite their widespread recreational use and therapeutic potential, the safety and pharmacokinetic properties of synthetic cannabinoids remain inadequately understood. This study examines the in vitro drug metabolism of a prominent class of SCs—indole-3-ylcycloalkyl ketones—by identifying and characterizing their metabolites. Human liver microsomes were used to investigate the metabolism of several SCs, including (2,2,3,3-tetramethylcyclopropyl)[1-(4,4,4-trifluorobutyl)-1H-indol-3-yl]-methanone (XLR-12), 1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl-methanone (A-796260), 1-[(1-methyl-2-piperidinyl)methyl]-1H-indol-3-yl-methanone (AB-005), 1-(5-fluoropentyl)-1H-indazol-3-yl-methanone (FAB-144), and 1-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-indol-3-yl-methanone (A-834735). Several time points were chosen to assist in elucidating the dynamics of metabolite formation. Generated metabolites were detected using liquid chromatography-mass spectrometry (LC-MS) and identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results revealed the formation of distinct metabolites and significant Phase 1 biotransformation processes, characterized by reduction, oxidation, and hydrolysis reactions. By characterizing the metabolic profiles of these compounds, this study identifies the common pathways of metabolisms for these drugs and the associated metabolites that should be monitored to indicate the consumption of the parent drug. This also demonstrates the potential of detecting these substances in biological samples. This information is crucial not only for forensic investigations and legal cases but also for evaluating safety in both recreational and potential therapeutic contexts. Additionally, these findings may guide the development of more effective screening methods and inform public health policies related to synthetic cannabinoid exposure.

Completion Date

2024

Semester

Fall

Committee Chair

Candice Bridge

Degree

Master of Science (M.S.)

College

College of Sciences

Department

Chemistry

Format

PDF

Identifier

DP0029700

Document Type

Thesis

Campus Location

Orlando (Main) Campus

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