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

Background: Intravenous 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. Objectives: To describe pharmacokinetics after intravenous and oral administrations with oil and micellar formulations and simulate different treatments. Study design: Single intravenous experiment and two-way randomised oral experiments, Latin-square design. Methods: Eight 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. Results: Intravenous 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 limitations: A small horse population was used (8 horses per trial). Conclusions and clinical importance: Oral 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.