{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T22:49:56Z","timestamp":1784242196740,"version":"3.55.0"},"reference-count":37,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T00:00:00Z","timestamp":1581379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["RTI2018-098885-B-100"],"award-info":[{"award-number":["RTI2018-098885-B-100"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The phytocannabinoid-based medicine Sativex\u00ae 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 na\u00efve 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), \u03949-tetrahydrocannabinol (\u03949-THC) and its metabolite 11-hydroxy-\u03949-THC. Maximal plasma concentrations of both \u03949-THC (Cmax = 18.5 ng\/mL) and CBD (Cmax = 10.5 ng\/mL) were achieved 2 h after administration in the single dose condition and at 1 h in the multiple dose treatment (\u03949-THC: Cmax = 24.5 ng\/mL; CBD: Cmax = 15.2 ng\/mL). 11-hydroxy-\u03949-THC, which is mainly formed in the liver from \u03949-THC, was almost undetected, which is consistent with the use of sublingual delivery. A potential progressive accumulation of both CBD and \u03949-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 na\u00efve dogs results in the expected pharmacokinetic profile, with maximal levels of phytocannabinoids detected at 1\u20132 h and suggested progressive accumulation after the multiple dose treatment.<\/jats:p>","DOI":"10.3390\/biom10020279","type":"journal-article","created":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T11:45:30Z","timestamp":1581421530000},"page":"279","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Pharmacokinetics of Sativex\u00ae in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2778-4805","authenticated-orcid":false,"given":"Mar\u00eda","family":"Fern\u00e1ndez-Trapero","sequence":"first","affiliation":[{"name":"Departamento de Medicina y Cirug\u00eda Animal, Facultad de Veterinaria, Universidad Complutense, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"P\u00e9rez-D\u00edaz","sequence":"additional","affiliation":[{"name":"Departamento de Medicina y Cirug\u00eda Animal, Facultad de Veterinaria, Universidad Complutense, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Espejo-Porras","sequence":"additional","affiliation":[{"name":"Instituto Universitario de Investigaci\u00f3n en Neuroqu\u00edmica, Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6260-3777","authenticated-orcid":false,"given":"Eva","family":"de Lago","sequence":"additional","affiliation":[{"name":"Instituto Universitario de Investigaci\u00f3n en Neuroqu\u00edmica, Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4490-0604","authenticated-orcid":false,"given":"Javier","family":"Fern\u00e1ndez-Ruiz","sequence":"additional","affiliation":[{"name":"Instituto Universitario de Investigaci\u00f3n en Neuroqu\u00edmica, Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.plefa.2018.11.016","article-title":"The endocannabinoid system: Overview of an emerging multi-faceted therapeutic target","volume":"140","author":"Chanda","year":"2019","journal-title":"Prostaglandins Leukot. Essent. Fatty Acids"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.plipres.2016.02.002","article-title":"Endocannabinoids and endocannabinoid-related mediators: Targets, metabolism and role in neurological disorders","volume":"62","author":"Iannotti","year":"2016","journal-title":"Prog. Lipid. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/978-3-319-20825-1_16","article-title":"Endocannabinoids and Cancer","volume":"231","author":"Velasco","year":"2015","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_4","first-page":"100","article-title":"Classical and nonclassical cannabinoids: Mechanism of action--brain binding","volume":"96","author":"Howlett","year":"1990","journal-title":"NIDA Res. Monogr"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/0166-2236(90)90124-S","article-title":"The cannabinoid receptor: Biochemical, anatomical and behavioral characterization","volume":"13","author":"Howlett","year":"1990","journal-title":"Trends Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0166-2236(98)01283-1","article-title":"Endocannabinoids: Endogenous cannabinoid receptor ligands with neuromodulatory action","volume":"21","author":"Melck","year":"1998","journal-title":"Trends Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S0024-3205(99)00281-7","article-title":"Discovery and characterization of endogenous cannabinoids","volume":"65","author":"Martin","year":"1999","journal-title":"Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/j.1369-1600.2008.00108.x","article-title":"Ligands that target cannabinoid receptors in the brain: From THC to anandamide and beyond","volume":"13","author":"Pertwee","year":"2008","journal-title":"Addict. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.1098\/rstb.2011.0381","article-title":"Targeting the endocannabinoid system with cannabinoid receptor agonists: Pharmacological strategies and therapeutic possibilities","volume":"367","author":"Pertwee","year":"2012","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.pharmthera.2011.09.002","article-title":"Phytocannabinoids as novel therapeutic agents in CNS disorders","volume":"133","author":"Hill","year":"2012","journal-title":"Pharmacol. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/j.1365-2125.2012.04341.x","article-title":"Cannabidiol for neurodegenerative disorders: Important new clinical applications for this phytocannabinoid?","volume":"75","author":"Sagredo","year":"2013","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1007\/s40265-017-0720-6","article-title":"\u03949-Tetrahydrocannabinol\/Cannabidiol oromucosal spray (Sativex\u00ae): A review in multiple sclerosis-related spasticity","volume":"77","author":"Keating","year":"2017","journal-title":"Drugs"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.msard.2017.06.015","article-title":"Sativex in the management of multiple sclerosis-related spasticity: An overview of the last decade of clinical evaluation","volume":"17","author":"Giacoppo","year":"2017","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1177\/1352458516643600","article-title":"Pharmacological management of spasticity in multiple sclerosis: Systematic review and consensus paper","volume":"22","author":"Comi","year":"2016","journal-title":"Mult. Scler."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1080\/17512433.2017.1292849","article-title":"Cannabinoids therapeutic use: What is our current understanding following the introduction of THC, THC:CBD oromucosal spray and others?","volume":"10","author":"Maccarrone","year":"2017","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"41","DOI":"10.2174\/157488912798842278","article-title":"Cannabinoids: Novel medicines for the treatment of Huntington\u2019s disease","volume":"7","author":"Sagredo","year":"2012","journal-title":"Recent Pat. CNS Drug Discov."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Cristino, L., Bisogno, T., and Di Marzo, V. (2019). Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat. Rev. Neurol., in press.","DOI":"10.1038\/s41582-019-0284-z"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1517\/14656566.9.7.1189","article-title":"Managing neuropathic pain with Sativex: A review of its pros and cons","volume":"9","author":"Perez","year":"2008","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Valastro, C., Campanile, D., Marinaro, M., Franchini, D., Piscitelli, F., Verde, R., Di Marzo, V., and Di Bello, A. (2017). Characterization of endocannabinoids and related acylethanolamides in the synovial fluid of dogs with osteoarthritis: A pilot study. BMC Vet. Res., 13.","DOI":"10.1186\/s12917-017-1245-7"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Abramo, F., Campora, L., Albanese, F., della Valle, M.F., Cristino, L., Petrosino, S., Di Marzo, V., and Miragliotta, V. (2014). Increased levels of palmitoylethanolamide and other bioactive lipid mediators and enhanced local mast cell proliferation in canine atopic dermatitis. BMC Vet. Res., 10.","DOI":"10.1186\/1746-6148-10-21"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Gesell, F.K., Zoerner, A.A., Brauer, C., Engeli, S., Tsikas, D., and Tipold, A. (2013). Alterations of endocannabinoids in cerebrospinal fluid of dogs with epileptic seizure disorder. BMC Vet. Res., 9.","DOI":"10.1186\/1746-6148-9-262"},{"key":"ref_22","first-page":"551","article-title":"Upregulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis","volume":"10","author":"Coates","year":"2017","journal-title":"Dis Model. Mech."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Freundt-Revilla, J., Heinrich, F., Zoerner, A., Gesell, F., Beyerbach, M., Shamir, M., Oevermann, A., Baumg\u00e4rtner, W., and Tipold, A. (2018). The endocannabinoid system in canine Steroid-Responsive Meningitis-Arteritis and Intraspinal Spirocercosis. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0187197"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s00418-018-1684-7","article-title":"Localization of cannabinoid receptors CB1, CB2, GPR55, and PPAR\u03b1 in the canine gastrointestinal tract","volume":"150","author":"Galiazzo","year":"2018","journal-title":"Histochem Cell Biol."},{"key":"ref_25","first-page":"1045","article-title":"Degenerative myelopathy in the aging German Shepherd dog: Clinical and pathologic findings","volume":"162","author":"Averill","year":"1973","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1016\/j.cvsm.2010.05.001","article-title":"Canine degenerative myelopathy","volume":"40","author":"Coates","year":"2010","journal-title":"Vet. Clin. N. Am. Small Anim. Pract."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.1073\/pnas.0812297106","article-title":"Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis","volume":"106","author":"Awano","year":"2009","journal-title":"Proc. Natl. Acad Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Freundt-Revilla, J., Kegler, K., Baumg\u00e4rtner, W., and Tipold, A. (2017). Spatial distribution of cannabinoid receptor type 1 (CB1) in normal canine central and peripheral nervous system. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181064"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.jchemneu.2016.02.002","article-title":"Immunohistochemical distribution of the cannabinoid receptor 1 and fatty acid amide hydrolase in the dog claustrum","volume":"74","author":"Pirone","year":"2016","journal-title":"J. Chem. Neuroanat."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"313","DOI":"10.3389\/fvets.2019.00313","article-title":"Cellular distribution of canonical and putative cannabinoid receptors in canine cervical dorsal root ganglia","volume":"6","author":"Chiocchetti","year":"2019","journal-title":"Front. Vet. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1111\/bph.14165","article-title":"Species-specific susceptibility to cannabis-induced convulsions","volume":"176","author":"Whalley","year":"2019","journal-title":"Br. J. Pharmacol"},{"key":"ref_32","unstructured":"(2020, February 10). Available online: www.lgcgroup.com\/pharma."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1111\/vec.12717","article-title":"Performance evaluation and validation of the animal trauma triage score and modified Glasgow Coma Scale with suggested category adjustment in dogs: A VetCOT registry study","volume":"28","author":"Ash","year":"2018","journal-title":"J. Vet. Emerg. Crit. Care"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1373\/clinchem.2010.152439","article-title":"Plasma cannabinoid pharmacokinetics following controlled oral \u03949-tetrahydrocannabinol and oromucosal cannabis extract administration","volume":"57","author":"Karschner","year":"2011","journal-title":"Clin. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1007\/s00228-012-1441-0","article-title":"A phase I study to assess the single and multiple dose pharmacokinetics of THC\/CBD oromucosal spray","volume":"69","author":"Stott","year":"2013","journal-title":"Eur. J. Clin. Pharmacol"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1002\/cbdv.200790152","article-title":"Human cannabinoid pharmacokinetics","volume":"4","author":"Huestis","year":"2007","journal-title":"Chem. Biodivers."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/bmc.1130030109","article-title":"Determination of \u03941-tetrahydrocannabinol in human fat biopsies from marihuana users by gas chromatography-mass spectrometry","volume":"3","author":"Johansson","year":"1989","journal-title":"Biomed. Chromatogr."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/2\/279\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:56:58Z","timestamp":1760173018000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/2\/279"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,11]]},"references-count":37,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["biom10020279"],"URL":"https:\/\/doi.org\/10.3390\/biom10020279","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,11]]}}}