Pharmacokinetics of Cannabidiol Following Intranasal, Intrarectal, and Oral Administration in Healthy Dogs

Abstract

The therapeutic potential of cannabidiol (CBD), a non-psychtropic component of the Cannabis sativa plant, is substantiated more and more. We aimed to determine the pharmacokinetic behavior of CBD after a single dose via intranasal (IN) and intrarectal (IR) administration in six healthy Beagle dogs age 3–8 years old, and compare to the oral administration route (PO). Standardized dosages applied for IN, IR and PO were 20, 100, and 100 mg, respectively. Each dog underwent the same protocol but received CBD through a different administration route. CBD plasma concentrations were determined by ultra-high performance liquid chromatography-tandem mass spectrometry before and at fixed time points after administration. Non-compartmental analysis was performed on the plasma concentration-time profiles. Plasma CBD concentrations after IR administration were below the limit of quantification. The mean area under the curve (AUC) after IN and PO CBD administration was 61 and 1,376 ng/mL*h, respectively. The maximal plasma CBD concentration (Cmax) after IN and PO CBD administration was 28 and 217 ng/mL reached after 0.5 and 3.5 h (Tmax), respectively. Significant differences between IN and PO administration were found in the Tmax (p = 0.04). Higher AUC and Cmax were achieved with 100 mg PO compared to 20 mg IN, but no significant differences were found when AUC (p = 0.09) and Cmax (p = 0.44) were normalized to 1 mg dosages. IN administration of CBD resulted in faster absorption when compared to PO administration. However, PO remains the most favorable route for CBD delivery due to its more feasible administration. The IR administration route is not advised for clinical application.

Strategies to Improve Cannabidiol Bioavailability and Drug Delivery

“…This indicates that CBD formulated as a nanoemulsion is potentially able to pass through the olfactory epithelium, thereby bypassing the blood–brain barrier and increasing the CBD concentration in the brain. In dogs, CBD administered intranasally (20 mg) resulted in a C max ~66% and an AUC ~22% of those of oral administration (100 mg) [ 26 ]. The T max with intranasal CBD ranged between 20 and 30 min among studies [ 26 , 65 , 66 ].…”

Cannabidiol for the Treatment of Brain Disorders: Therapeutic Potential and Routes of Administration

“…In addition, it has a well-vascularized and thin mucosal membrane [ 155 ], allowing passive diffusion into the bloodstream and enhancing drug absorption [ 149 , 156 ]. A recent study in dogs demonstrated a sevenfold faster absorption via the intranasal route compared to the oral route (intranasal vs oral t max = 0.5 vs 3.5 h) [ 157 ]. Comparatively, various nasal formulations were developed by Paudel et al who reported rapid CBD nasal absorption for all the formulations (t max ≤ 10 min) in rats [ 142 ].…”

“…Although first pass metabolism is still possible via the hepatic portal vein into the upper part of the rectum, it can be avoided if the drug is administered to the lower rectum as absorption occurs via the inferior and middle haemorrhoidal veins, which are non-hepatic [ 132 ]. An attempt to study the PK profile of 100 mg CBD suppositories in healthy dogs yielded plasma CBD levels that were lower than the limit of quantification, so the data could not be analyzed [ 157 ]. Despite that, some studies supported the use of rectal delivery of anticonvulsants, such as diazepam and levetiracetam, for fast and effective seizure treatment [ 171 , 172 ].…”

Pharmacokinetics behavior of four cannabidiol preparations following single oral administration in dogs

“…Several dosage forms of CBD have been studied in animals ( 11 ), such as liquid oil-based, capsules, soft chew ( 15–17 ), microencapsulated oil beads and transdermal cream ( 18 ), intranasal, and as a suppository ( 19 ). Nowadays, there are variety of CBD products available for pets, with growing consumption in the global market ( 11 , 20 ).…”