Matrix and nanoformulation-dependent bioavailability of cannabinoids in the Caco-2 Model

Phytocannabinoids are bioactive plant-derived compounds with promising therapeutic potential [ 1 ], but their oral bioavailability remains limited and variable [ 2 ]. Understanding their absorption mechanisms is essential for optimizing formulation strategies and predicting pharmacokinetic behavior. The bioavailability of various cannabinoids (10) was assessed in vitro using the Caco-2 cellular model. Permeability coefficients (Papp) were determined for individual cannabinoids, both in pure form and with added cannabis-derived matrices. Neutral cannabinoids showed significantly increased permeability in the presence of terpenic matrix components, while cannabinoid acids did not exhibit matrix-induced permeability changes. Additional analyses assessed cannabinoid distribution across the apical medium, Caco-2 cells, and basolateral compartment. Neutral cannabinoids primarily accumulated in cells (~57%), whereas acids remained mostly in the apical medium with minimal cellular uptake (~7%).In a follow-up experiment focused on nanoformulation, only cannabidio (CBD) and its acid (CBDA) were tested. Nanoformulated CBD showed markedly reduced accumulation in Caco-2 cells, reaching levels similar to CBDA, likely due to micelle formation. Interestingly, CBDA maintained better basolateral passage even in nanoform, suggesting different intracellular processing mechanisms. These findings highlight the importance of chemical structure, formulation, and matrix effects in modulating the intestinal absorption of phytocannabinoids. Acknowledgement This work was supported by the METROFOOD-CZ Research Infrastructure ( https://metrofood.cz ), supported by the Ministry of Education, Youth and Sports of the Czech Republic (Project No. LM2023064) and the grant of Specific university research – A1_FPBT_2024_006 and the Czech Science Foundation (GAČR) – 22-20860S. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany