Metabolic pathways, pharmacokinetic, and brain neurochemicals effects of capsaicin: Comprehensively insights from in vivo studies

Background

Capsaicin (CAP), a prominent component of chili pepper known for its potent agonistic effects on TRPV1, has attracted significant attention for its diverse physiological effects. Nevertheless, there remains a paucity of data concerning its in vivo distribution, metabolism, pharmacodynamic properties, and influence on the metabolic profile of the brain.

Methods

Stable isotope tracing, in vitro enzyme incubation, microdialysis coupled with UHPLC-MS/MS techniques were employed to investigate the in vivo metabolic pathways, distribution, and pharmacokinetic properties of CAP, and the potential biases in metabolic pathways was elucidate through molecular docking. Furthermore, the effect of CAP on brain metabolic profiles was assessed using untargeted metabolomics, and spatial visualization analysis was conducted through mass spectrometry imaging.

Results

CAP was distributed predominantly in the kidneys, with lower content in the liver, heart, lungs, brain, and spleen following peripheral administration, and the absorption half-life in the body was about 20 min. CAP primarily underwent alkyl terminal dehydrogenation, hydroxylation, and macrocyclization metabolic pathways under the action of CYP2C9, CYP2C19 and CYP2D6, resulting in at least four metabolites. Among them, the hydroxylation products were main metabolites and the dehydrogenation product 16,17-dihydrocapsaicin could interact with the key binding sites Leu515 and Thr550 of TRPV1 like CAP. CAP quickly diffused to various brain regions and the metabolic characteristics in the striatum were relatively different from that in the blood. The distribution of CAP in the brain primarily triggered the release of neurotransmitters in areas associated with reward, cognition, and memory. Both acute and chronic exposure to CAP elevated amino acid levels in cortical regions, while producing contrasting effects on nucleotide metabolites.

Conclusion

This study offers an initial in-depth analysis of the distribution patterns, metabolic pathways and pharmacodynamic properties of CAP in the body and brain. These findings established a basis for further studies on CAP's pharmacology properties and its influence on the central nervous system.