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Pharmacokinetics of Sativex(®) in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders

The phytocannabinoid-based medicine Sativex(®) is currently marketed for the treatment of spasticity and pain in multiple sclerosis patients and is being investigated for other central and peripheral pathological conditions. It may also serve in Veterinary Medicine for the treatment of domestic anim...

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Autores principales: Fernández-Trapero, María, Pérez-Díaz, Carmen, Espejo-Porras, Francisco, de Lago, Eva, Fernández-Ruiz, Javier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072526/
https://www.ncbi.nlm.nih.gov/pubmed/32054131
http://dx.doi.org/10.3390/biom10020279
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author Fernández-Trapero, María
Pérez-Díaz, Carmen
Espejo-Porras, Francisco
de Lago, Eva
Fernández-Ruiz, Javier
author_facet Fernández-Trapero, María
Pérez-Díaz, Carmen
Espejo-Porras, Francisco
de Lago, Eva
Fernández-Ruiz, Javier
author_sort Fernández-Trapero, María
collection PubMed
description The phytocannabinoid-based medicine Sativex(®) is currently marketed for the treatment of spasticity and pain in multiple sclerosis patients and is being investigated for other central and peripheral pathological conditions. It may also serve in Veterinary Medicine for the treatment of domestic animals, in particular for dogs affected by different pathologies, including human-like pathological conditions. With the purpose of assessing different dosing paradigms for using Sativex in Veterinary Medicine, we investigated its pharmacokinetics when administered to naïve dogs via sublingual delivery. In the single dose arm of the study, adult Beagle dogs were treated with 3 consecutive sprays of Sativex, and blood samples were collected at 12 intervals up to 24 h later. In the multiple dose arm of the study, Beagle dogs received 3 sprays daily for 14 days, and blood samples were collected for 24 h post final dose. Blood was used to obtain plasma samples and to determine the levels of cannabidiol (CBD), Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and its metabolite 11-hydroxy-Δ(9)-THC. Maximal plasma concentrations of both Δ(9)-THC (C(max) = 18.5 ng/mL) and CBD (C(max) = 10.5 ng/mL) were achieved 2 h after administration in the single dose condition and at 1 h in the multiple dose treatment (Δ(9)-THC: C(max) = 24.5 ng/mL; CBD: C(max) = 15.2 ng/mL). 11-hydroxy-Δ(9)-THC, which is mainly formed in the liver from Δ(9)-THC, was almost undetected, which is consistent with the use of sublingual delivery. A potential progressive accumulation of both CBD and Δ(9)-THC was detected following repeated exposure, with maximum plasma concentrations for both cannabinoids being achieved following multiple dose. Neurological status, body temperature, respiratory rate and some hemodynamic parameters were also recorded in both conditions, but in general, no changes were observed. In conclusion, this study demonstrates that single or multiple dose sublingual administration of Sativex to naïve dogs results in the expected pharmacokinetic profile, with maximal levels of phytocannabinoids detected at 1–2 h and suggested progressive accumulation after the multiple dose treatment.
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spelling pubmed-70725262020-03-19 Pharmacokinetics of Sativex(®) in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders Fernández-Trapero, María Pérez-Díaz, Carmen Espejo-Porras, Francisco de Lago, Eva Fernández-Ruiz, Javier Biomolecules Article The phytocannabinoid-based medicine Sativex(®) is currently marketed for the treatment of spasticity and pain in multiple sclerosis patients and is being investigated for other central and peripheral pathological conditions. It may also serve in Veterinary Medicine for the treatment of domestic animals, in particular for dogs affected by different pathologies, including human-like pathological conditions. With the purpose of assessing different dosing paradigms for using Sativex in Veterinary Medicine, we investigated its pharmacokinetics when administered to naïve dogs via sublingual delivery. In the single dose arm of the study, adult Beagle dogs were treated with 3 consecutive sprays of Sativex, and blood samples were collected at 12 intervals up to 24 h later. In the multiple dose arm of the study, Beagle dogs received 3 sprays daily for 14 days, and blood samples were collected for 24 h post final dose. Blood was used to obtain plasma samples and to determine the levels of cannabidiol (CBD), Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and its metabolite 11-hydroxy-Δ(9)-THC. Maximal plasma concentrations of both Δ(9)-THC (C(max) = 18.5 ng/mL) and CBD (C(max) = 10.5 ng/mL) were achieved 2 h after administration in the single dose condition and at 1 h in the multiple dose treatment (Δ(9)-THC: C(max) = 24.5 ng/mL; CBD: C(max) = 15.2 ng/mL). 11-hydroxy-Δ(9)-THC, which is mainly formed in the liver from Δ(9)-THC, was almost undetected, which is consistent with the use of sublingual delivery. A potential progressive accumulation of both CBD and Δ(9)-THC was detected following repeated exposure, with maximum plasma concentrations for both cannabinoids being achieved following multiple dose. Neurological status, body temperature, respiratory rate and some hemodynamic parameters were also recorded in both conditions, but in general, no changes were observed. In conclusion, this study demonstrates that single or multiple dose sublingual administration of Sativex to naïve dogs results in the expected pharmacokinetic profile, with maximal levels of phytocannabinoids detected at 1–2 h and suggested progressive accumulation after the multiple dose treatment. MDPI 2020-02-11 /pmc/articles/PMC7072526/ /pubmed/32054131 http://dx.doi.org/10.3390/biom10020279 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fernández-Trapero, María
Pérez-Díaz, Carmen
Espejo-Porras, Francisco
de Lago, Eva
Fernández-Ruiz, Javier
Pharmacokinetics of Sativex(®) in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders
title Pharmacokinetics of Sativex(®) in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders
title_full Pharmacokinetics of Sativex(®) in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders
title_fullStr Pharmacokinetics of Sativex(®) in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders
title_full_unstemmed Pharmacokinetics of Sativex(®) in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders
title_short Pharmacokinetics of Sativex(®) in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders
title_sort pharmacokinetics of sativex(®) in dogs: towards a potential cannabinoid-based therapy for canine disorders
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072526/
https://www.ncbi.nlm.nih.gov/pubmed/32054131
http://dx.doi.org/10.3390/biom10020279
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