Pharmacokinetics and oral bioavailability of cannabidiol in horses after intravenous and oral administration with oil and micellar formulations

Abstract

BackgroundIntravenous pharmacokinetics and oral bioavailability of cannabidiol (CBD) with different formulations have not been investigated in horses and may represent a starting point for clinical studies.ObjectivesTo describe pharmacokinetics after intravenous and oral administrations with oil and micellar formulations and simulate different treatments.Study designSingle intravenous experiment and two‐way randomised oral experiments, Latin‐square design.MethodsEight healthy horses received intravenous CBD at 1.00 mg/kg dose, oral CBD in sesame oil and in micellar formulation, both at 10.00 mg/kg. Concentrations were measured using LC–MS/MS and fitted by nonlinear mixed effect modelling. Parameters obtained were used to simulate single and multiple treatments at steady state.ResultsIntravenous and oral concentrations were simultaneously fitted using a three‐compartment model. Final estimates indicate that CBD has a volume of distribution of 36 L/kg associated with a systemic clearance of 1.46 L/h/kg and half‐lives ranged between 24 and 34 h. Oral bioavailability was close to 14% for both oral administrations. Simulated dose regimen of CBD every 12 and 24 h predicted similar percentages to reach effective plasma concentration with both oral formulation at 10.00 mg/kg.Main limitationsA small horse population was used (8 horses per trial).Conclusions and clinical importanceOral bioavailability was low at the doses studied but fell within the range described for horse and other species. CBD had a high steady‐state volume of distribution, a high clearance and long half‐lives. No adverse reactions were detected at any dose or route. The micellar formulation showed a faster absorption and higher concentration peak, while the oil formulation presented lower levels, but more maintained over time. Simulations predicted that both could be useful in multiple oral dose treatments. These results indicated that CBD could be of interest, but further studies are needed to evaluate its clinical use in horses.

Pharmacokinetic modelling of orally administered cannabidiol and implications for medication control in horses

“…Like in other equine and small animal investigations, the pharmacokinetic analysis showed a rapid increase of CBD in serum following oral administration ( 15 , 16 , 28 , 29 , 50 – 55 ). The values for C max were similar to those calculated in other studies ( 28 – 31 , 33 ). In contrast, the AUC 0–12 h values obtained here differ significantly.…”

An Intravenous Pharmacokinetic Study of Cannabidiol Solutions in Piglets through the Application of a Validated Ultra-High-Pressure Liquid Chromatography Coupled to Tandem Mass Spectrometry Method for the Simultaneous Quantification of CBD and Its Carboxylated Metabolite in Plasma

“…Because CBD is a BCS II molecule, it is challenging to formulate a parenteral solution. A few authors have studied the intravenous kinetics of CBD by injecting Cremophor ® emulsion, suspensions containing Tween ® , or propylene–ethanol solutions in mice or humans [ 35 , 36 , 37 ]. In our study, the cyclodextrin (CD) strategy was chosen in accordance with previous work in our laboratory [ 16 ].…”

Behavioral observations, heart rate and cortisol monitoring in horses following multiple oral administrations of a cannabidiol containing paste (part 2/2)

“…( 8 , 66–71 ). Two studies found C max levels of 51 ng/mL CBD in serum following oral administration of 2 mg CBD/kg SID for 7 days ( 67 , 70 ), and C max levels of 55.7 ng/mL CBD in serum following a single oral dose of 10 mg CBD/kg ( 72 ). The C max levels of 38.4 ± 8.9 ng/mL in serum reported during the current study ( 63 ) are therefore in line with previous reports, and comparatively high ( 70 ).…”

“…Future studies may also include more detailed assessments of HRV parameters including the parasympathetic tone activity (PTA) index. Oral dosing using different formulations such as micellar formulation should also be considered ( 72 ). Clinical studies as have been performed with dogs ( 4 ) are of interest to further assess the potential use of CBD in equine medicine.…”