Pharmacokinetic Modeling of the "Nose-to-Brain" Pathway as Demonstrated by Intranasal Administration of...

Background/Objectives: Cannabidiol is a non-psychoactive substance that possesses properties suitable for the treatment of several disorders related to the central nervous system. However, successful administration of cannabidiol remains challenging due to low and variable bioavailability and potential adverse effects. Intranasal delivery of cannabidiol may help overcome these limitations, but the pharmacokinetics of such administration has not been fully established. Methods: Starch-based cannabidiol-loaded nanoparticles were used as carriers and were administered to rats via the intranasal route. Cannabidiol levels in plasma and the brain were examined at different time points and compared to cannabidiol levels in plasma and the brain following intravenous administration of cannabidiol solution for injection. Pharmacokinetic parameters were calculated for each delivery route, and a pharmacokinetic model was fitted for the intranasal administration. Results: Intranasal administration resulted in a bioavailability of 47.9%. Systemic absorption accounted for 44% of the absorbed drug, while 56% was absorbed by direct brain entry. Intranasal administration resulted in rapid brain penetration with a brain t_max of 10 min and demonstrated a brain bioavailability of 28.5% compared to bioavailability after intravenous bolus injection of cannabidiol solution. Conclusions: Intranasal administration of cannabidiol-loaded nanoparticles was found to be effective for the delivery of cannabidiol to the brain with significantly lower systemic exposure compared to intravenous administration. A proposed pharmacokinetic model was found to be appropriate in describing and predicting the disposition pathways following intranasal administration, especially when designing drug delivery systems for brain targeting.