Pharmacokinetic Properties of the Novel Synthetic Cannabinoid 5F-APINAC and Its Influence on Metabolites Associated with Neurotransmission in Rabbit Plasma.

Ksenia M Shestakova,Alexey Kukharenko,Roman M Kuznetsov,Svetlana A Appolonova,Natalia V Mesonzhnik,Natalia L Bochkareva,Alex Brito,Alexey V Lyundup,Elizaveta G Appolonova,Pavel A Markin,Franco Tagliaro,Andrey A Nedorubov,Natalia E Moskaleva

doi:10.3390/ph14070668

Abstract

The strong psychoactive effects of synthetic cannabinoids raise the need for the deeper studying of their neurometabolic effects. The pharmacokinetic properties of 5F-APINAC and its influence on metabolomics profiles associated with neurotransmission were investigated in rabbit plasma. Twelve rabbits divided into three groups received 1-mL 5F-APINAC at 0.1, 1 and 2 mg/kg. The intervention groups were compared with the controls. Sampling was performed at nine time points (0–24 h). Ultra-high-performance liquid chromatography–tandem mass spectrometry was used. The pharmacokinetics were dose-dependent (higher curve at a higher dose) with a rapid biotransformation, followed by gradual elimination within 24 h. The tryptophan concentrations abruptly decreased (p < 0.05) in all tested groups, returning to the basal levels after 6 h. 5-hydroxylindole acetic acid increased (p < 0.05) in the controls, but this trend was absent in the treated groups. The aspartic acid concentrations were elevated (p < 0.001) in the treated groups. L-kynurenine was elevated (p < 0.01) in the intervention groups receiving 1 mg/kg to 2 mg/kg. Dose-dependent elevations (p < 0.01) were found for kynurenic acid, xanthurenic acid and quinolinic acid (p < 0.01), whereas the anthranilic acid trends were decreased (p < 0.01). The indole-3-propionic acid and indole-3-carboxaldehyde trends were elevated (p < 0.05), whereas the indole-3-lactic acid trajectories were decreased (p < 0.01) in the intervention groups. 5F-APINAC administration had a rapid biotransformation and gradual elimination. The metabolites related to the kynurenine and serotonergic system/serotonin pathways, aspartic acid innervation system and microbial tryptophan catabolism were altered.

Highlights

The illegal use of synthetic cannabinoids (SCs) has been growing exponentially [1,2,3].These drugs represent one of the largest groups of new psychoactive substances (NPS), gaining significant importance in clinical and forensic toxicology
The pharmacokinetics profile was characterized by being dose-dependent with rapid biotransformation within the first five hours after drug administration, followed by gradual elimination within 24 h (Figure 1)
The present study reported the pharmacokinetics properties of the new SCs 5FAPINAC and a novel and original analysis of the changes of the plasma profiles of tryptophan metabolites observed in the plasma of rabbits after intravenous administration of this drug of abuse

Summary

Introduction

The illegal use of synthetic cannabinoids (SCs) has been growing exponentially [1,2,3]. These drugs represent one of the largest groups of new psychoactive substances (NPS), gaining significant importance in clinical and forensic toxicology. SCs are characterized by a strong affinity to cannabinoid receptors (CB1 and CB2) and by a highly lipophilic nature. CB1 receptors are often localized at axon terminals, and their activation leads to the inhibition of neurotransmitter releases [5]. These receptors may interact with ion channels, exploiting their inhibition or activation [6]

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Conclusion