In vivo and in vitro metabolism of the novel synthetic cannabinoid 5F-APINAC

Appolonova, Svetlana A.; Palacio, Covadonga; Shestakova, Ksenia; Mesonzhnik, Natalia V.; Brito, Alex; Kuznetsov, Roman M.; Markin, Pavel A.; Bochkareva, N. L.; Burmykin, D. A.; Ovcharov, M. V.; Musile, Giacomo; Tagliaro, Franco; Savchuk, S. A.

doi:10.1007/s11419-019-00503-z

Cited by 3 publications

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“…The novel SC 5F-APINAC represents a recently emerged NPS belonging to an adamantylindazole structural class [ 7 ]. The in vitro and in vivo metabolism of 5F-APINAC in rats has been described postulating the rapid hydrolysis and hydroxylation of the parent drug with a consequent formation of its main metabolites—5F-pentylidazol carboxylic acid and hydroxyl derivatives [ 7 ]. Notably, due to the rapid metabolism of 5F-APINAC, the parent drug has not been detected so far in urine.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Inevitably, it is necessary to consider the ethical bottleneck to conduct studies in humans without a clear understanding of the drug´s toxicology. In this way, alternative models have been used to circumvent the use of human volunteers in metabolism studies [10][11][12]. Among them, zebrafish (Danio rerio) has already demonstrated advantages over in vitro and classical animal models [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Metabolism of synthetic cathinones through the zebrafish water tank model: a promising tool for forensic toxicology laboratories

et al. 2020

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The aim of this study was to identify in vivo phase I metabolites of five psychoactive substances: N-ethylpentylone, ethylone, methylone, α-PVP and 4-CDC, using the in house developed experimental setup zebrafish (Danio rerio) water tank (ZWT). High-resolution mass spectrometry allowed for metabolite identification. A pilot study of reference standard collection of N-ethylpentylone from the water tank was conducted. Methods ZWT consisted in 8 fish placed in a 200 mL recipient-containing water for a single cathinone. Experiments were performed in triplicate. Water tank samples were collected after 8 h and pretreated through solid-phase extraction. Separation and accurate-mass spectra of metabolites were obtained using liquid chromatography-high resolution tandem mass spectrometry. Results Phase I metabolites of α-PVP were identified, which were formed involving ketone reduction, hydroxylation, and 2″-oxo-pyrrolidine formation. The lactam derivative was the major metabolite observed for α-PVP in ZWT. N-Ethylpentylone and ethylone were transformed into phase I metabolites involving reduction, hydroxylation, and dealkylation. 4-CDC was transformed into phase I metabolites, reported for the first time, involving N-dealkylation, N,N-bis-dealkylation and reduction of the ketone group, the last one being the most intense after 8 h of the experiment. Conclusions ZWT model indicated to be very useful to study the metabolism of the synthetic cathinones, such as N-ethylpentylone, ethylone, α-PVP and 4-CDC. Methylone seems to be a potent CYP450 inhibitor in zebrafish. More experiments are needed to better evaluate this issue. Finally, this approach was quite simple, straightforward, extremely low cost, and fast for "human-like" metabolic studies of synthetic cathinones. Keywords Synthetic cathinones • Zebrafish • In vivo metabolism • High-resolution mass spectrometry • Human-like experimental model • Reference standard collection in zebrafish water tank Electronic supplementary material The online version of this article (

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Short- and long-term exposures of the synthetic cannabinoid 5F-APINAC induce metabolomic alterations associated with neurotransmitter systems and embryotoxicity confirmed by teratogenicity in zebrafish

Markin

Brito

Moskaleva

et al. 2021

Comparative Biochemistry and Physiology Part C: Toxicology &

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In vivo and in vitro metabolism of the novel synthetic cannabinoid 5F-APINAC

Cited by 3 publications

References 20 publications

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

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

Metabolism of synthetic cathinones through the zebrafish water tank model: a promising tool for forensic toxicology laboratories

Short- and long-term exposures of the synthetic cannabinoid 5F-APINAC induce metabolomic alterations associated with neurotransmitter systems and embryotoxicity confirmed by teratogenicity in zebrafish

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