Metabolism, pharmacokinetics, and bioavailability of cannabigerol in horses following intravenous and oral administration with micellar and oil formulations.
Abstract: Cannabigerol (CBG) is a non-psychoactive cannabinoid with growing interest in veterinary medicine; however, its pharmacokinetic profile in horses remains unknown. Understanding its absorption, distribution, metabolism, and elimination is essential to optimizing dosing strategies and evaluating its potential for clinical use in equine patients. Unassigned: A prospective crossover study was conducted in eight healthy adult horses to assess the metabolism and the pharmacokinetics after intravenous (IV) administration at 1 mg/kg and oral administrations at 10 mg/kg with two formulations (micellar and oil). Plasma concentrations of CBG and its main metabolite, CBG-glucuronide (CBG-G), were analyzed by LC-MSMS and modeled using a non-linear mixed effects model with MonolixSuite®. The model estimated the bioavailability, metabolic conversion, and absorption parameters. Furthermore, Monte Carlo simulations were performed to predict and evaluate the drug exposure after a multiple-dose regimen. Unassigned: High metabolism was observed with the formation of epoxy and hydroxy metabolites via phase I reactions, and CBG-G was the main metabolite from phase II reactions (75% of biotransformation). After IV administration, CBG showed a high volume of distribution (V = 74 L/kg) and systemic clearance (Cl = 1.67 L/h/kg), with a terminal half-life of approximately 29 h. The oral bioavailability was estimated at 28% between formulations, and an extensive presystemic metabolism was obtained with metabolite/parent AUC ratios exceeding 50. The micellar formulation showed a shorter time to achieve maximum concentration (T) and faster absorption as compared to the oil formulation. The Monte Carlo simulations of multiple oral doses (10 mg/kg q24 h for 14 days) predicted differences between formulations. No adverse clinical effects were observed during the study. Unassigned: This study shows the first evaluation of the metabolism and pharmacokinetics of CBG in horses after IV and oral administration. The findings highlight extensive metabolite formation with significant glucuronidation, a large distribution volume, and high clearance. While both oral formulations produced similar systemic exposure, the faster absorption with the micellar formulation may inform clinical decisions depending on therapeutic goals. These data support the potential use of CBG in horses and offer a foundation for further studies in equine medicine.
Copyright © 2025 Serrano-Rodríguez, Miraz, Saitua, Díez de Castro, Ledesma-Escobar, Ferreiro-Vera, Priego-Capote, Sánchez de Medina and Sánchez de Medina.
Publication Date: 2025-10-29 PubMed ID: 41234397PubMed Central: PMC12607281DOI: 10.3389/fvets.2025.1688214Google Scholar: Lookup
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Summary
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Overview
- This study investigated how cannabigerol (CBG), a non-psychoactive cannabinoid, is absorbed, metabolized, distributed, and cleared in horses after intravenous and oral administration using two formulations (micellar and oil).
- The research provided detailed pharmacokinetic data, including the bioavailability and metabolism of CBG, and evaluated its potential for clinical use in equine veterinary medicine.
Study Purpose and Importance
- Cannabigerol (CBG) is gaining interest as a veterinary therapeutic agent, but its behavior in horses—such as how the drug is absorbed, metabolized, distributed, and eliminated—was previously unknown.
- Understanding these pharmacokinetic properties is essential for developing effective dosing strategies and assessing CBG’s safety and efficacy in horses.
Methodology
- A prospective crossover design was used with eight healthy adult horses to ensure each horse received all treatments, minimizing individual variability.
- CBG was administered in two ways:
- Intravenous (IV) injection at a dose of 1 mg/kg to assess direct systemic pharmacokinetics without absorption barriers.
- Oral administration at 10 mg/kg using two different formulations: micellar and oil, to evaluate absorption differences and oral bioavailability.
- Plasma concentrations of CBG and its main metabolite, CBG-glucuronide (CBG-G), were measured using advanced liquid chromatography-mass spectrometry (LC-MSMS) for accurate quantification.
- Pharmacokinetic modeling was performed using a non-linear mixed effects model with MonolixSuite®, allowing estimation of key parameters such as bioavailability, absorption rates, metabolic conversion rates, volume of distribution, and clearance.
- Monte Carlo simulations were conducted to predict the drug exposure after repeated oral dosing (10 mg/kg every 24 hours for 14 days), assessing steady-state pharmacokinetics and differences between formulations.
Main Findings: Metabolism
- CBG underwent extensive metabolism in horses, primarily through two phases:
- Phase I reactions: formation of epoxy and hydroxy metabolites.
- Phase II reactions: dominant metabolite was CBG-glucuronide (CBG-G), which accounted for about 75% of total biotransformation, indicating significant glucuronidation.
- The high metabolite formation suggested substantial presystemic metabolism, especially after oral administration.
Main Findings: Pharmacokinetics
- After IV administration:
- CBG showed a very high volume of distribution (74 L/kg), indicating widespread distribution into tissues beyond the blood plasma.
- Systemic clearance was high (1.67 L/h/kg), reflecting rapid elimination from systemic circulation.
- Terminal half-life was approximately 29 hours, suggesting relatively long persistence in the body after IV dosing.
- After oral administration:
- Oral bioavailability was about 28% for both micellar and oil formulations, implying moderate absorption but extensive first-pass metabolism.
- The ratio of metabolite to parent drug AUC values exceeded 50, reinforcing the degree of presystemic metabolism.
- The micellar formulation resulted in faster absorption and shorter time to reach maximum plasma concentration (Tmax) compared to the oil formulation.
Monte Carlo Simulations for Multiple Dosing
- Simulated multiple-dose scenarios (10 mg/kg every 24 h for 14 days) predicted differences in drug exposure between micellar and oil formulations.
- The faster absorption of the micellar formulation may lead to quicker onset of action, which could be beneficial depending on therapeutic goals.
- These simulations help anticipate steady-state levels and guide dosing regimen design.
Safety Observations
- No adverse clinical effects were observed during the study period for any administration route or formulation.
- This suggests CBG is well tolerated in healthy adult horses at investigated doses.
Conclusions and Implications
- This work represents the first comprehensive pharmacokinetic and metabolism evaluation of CBG in horses.
- Key pharmacokinetic characteristics identified include:
- Extensive metabolism primarily via glucuronidation (phase II).
- Large distribution volume indicating wide tissue dissemination.
- High systemic clearance resulting in substantial elimination capacity.
- Oral bioavailability is moderate and similar between micellar and oil formulations, but micellar shows advantages in absorption speed.
- Faster absorption via micellar formulations may be preferable in clinical situations requiring rapid effects, while both formulations achieve comparable overall exposure.
- These findings establish a pharmacokinetic foundation to support potential therapeutic use of CBG in equine medicine and highlight areas for further investigation, such as efficacy trials or different dosing strategies.
Cite This Article
APA
Serrano-Rodríguez JM, Miraz R, Saitua A, Díez de Castro E, Ledesma-Escobar C, Ferreiro-Vera C, Priego-Capote F, Sánchez de Medina V, Sánchez de Medina A.
(2025).
Metabolism, pharmacokinetics, and bioavailability of cannabigerol in horses following intravenous and oral administration with micellar and oil formulations.
Front Vet Sci, 12, 1688214.
https://doi.org/10.3389/fvets.2025.1688214 Publication
Researcher Affiliations
- Pharmacology Area, Department of Nursing, Pharmacology and Physiotherapy, Veterinary Faculty, University of Córdoba, Córdoba, Spain.
- Veterinary Clinical Hospital, University of Cordoba, Córdoba, Spain.
- Department of Animal Medicine and Surgery, Veterinary Faculty, University of Cordoba, Córdoba, Spain.
- Equine Sports Medicine Center CEMEDE, Department of Animal Medicine and Surgery, Veterinary Faculty, University of Córdoba, Córdoba, Spain.
- Veterinary Clinical Hospital, University of Cordoba, Córdoba, Spain.
- Equine Sports Medicine Center CEMEDE, Department of Animal Medicine and Surgery, Veterinary Faculty, University of Córdoba, Córdoba, Spain.
- Veterinary Clinical Hospital, University of Cordoba, Córdoba, Spain.
- Department of Analytical Chemistry, Science Faculty, University of Córdoba, Córdoba, Spain.
- Chemical Institute for Energy and Environment (IQUEMA), Campus of Rabanales, University of Córdoba, Córdoba, Spain.
- Phytoplant Research S.L.U., Córdoba, Spain.
- Department of Analytical Chemistry, Science Faculty, University of Córdoba, Córdoba, Spain.
- Phytoplant Research S.L.U., Córdoba, Spain.
- Veterinary Clinical Hospital, University of Cordoba, Córdoba, Spain.
- Department of Animal Medicine and Surgery, Veterinary Faculty, University of Cordoba, Córdoba, Spain.
- Equine Sports Medicine Center CEMEDE, Department of Animal Medicine and Surgery, Veterinary Faculty, University of Córdoba, Córdoba, Spain.
Conflict of Interest Statement
CF-V and VS are Phytoplant Research employees, manufacturers of cannabigerol, the drug investigated in this research. The Phytoplant Research S.L.U. company intends to apply for a patent related to the micellar formulation used in this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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