Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive–compulsive behaviour
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Phytocannabinoids are useful therapeutics for multiple applications including treatments of constipation, malaria, rheumatism, alleviation of intraocular pressure, emesis, anxiety and some neurological and neurodegenerative disorders. Consistent with these medicinal properties, extracted cannabinoids have recently gained much interest in research, and some are currently in advanced stages of clinical testing. Other constituents of Cannabis sativa, the hemp plant, however, remain relatively unexplored in vivo. These include cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (Δ9-THCV) and cannabigerol (CBG).
Objectives and methods
We here determined pharmacokinetic profiles of the above phytocannabinoids after acute single-dose intraperitoneal and oral administration in mice and rats. The pharmacodynamic–pharmacokinetic relationship of CBD (120 mg/kg, ip and oral) was further assessed using a marble burying test in mice.
All phytocannabinoids readily penetrated the blood–brain barrier and solutol, despite producing moderate behavioural anomalies, led to higher brain penetration than cremophor after oral, but not intraperitoneal exposure. In mice, cremophor-based intraperitoneal administration always attained higher plasma and brain concentrations, independent of substance given. In rats, oral administration offered higher brain concentrations for CBD (120 mg/kg) and CBDV (60 mg/kg), but not for Δ9-THCV (30 mg/kg) and CBG (120 mg/kg), for which the intraperitoneal route was more effective. CBD inhibited obsessive–compulsive behaviour in a time-dependent manner matching its pharmacokinetic profile.
These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions.
KeywordsPhytocannabinoids Systemic administration Bioavailability Area under curve Elimination half-life Pharmacokinetic Pharmacodynamic Rats Mice
This work was partly supported by a collaboration between GW Pharmaceuticals and Otsuka Pharma. Furthermore, and we are indebted to Drs. T Kikuchi for comments on an earlier draft of this manuscript.
- Barna I, Till I, Haller J (2009) Blood, adipose tissue and brain levels of the cannabinoid ligands WIN-55,212 and SR-141716A after their intraperitoneal injection in mice: compound-specific and area-specific distribution within the brain. Eur Neuropsychopharmacol 19:533–541. doi: 10.1016/j.euroneuro.2009.02.001 PubMedCrossRefGoogle Scholar
- Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Moriello AS, Davis JB, Mechoulam R, Di Marzo V (2001) Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 134:845–852. doi: 10.1038/sj.bjp.0704327 PubMedCrossRefGoogle Scholar
- Bolognini D, Costa B, Maione S, Comelli F, Marini P, Di Marzo V, Parolaro D, Ross RA, Gauson LA, Cascio MG, Pertwee RG (2010) The plant cannabinoid delta9-tetrahydrocannabivarin can decrease signs of inflammation and inflammatory pain in mice. Br J Pharmacol 160:677–687. doi: 10.1111/j.1476-5381.2010.00756.x PubMedCrossRefGoogle Scholar
- Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee RG (2010) Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. Br J Pharmacol 159:129–141. doi: 10.1111/j.1476-5381.2009.00515.x PubMedCrossRefGoogle Scholar
- Claassen V (1994) Neglected factors in pharmacology and neuroscience research. Elsevier, AmsterdamGoogle Scholar
- Gaoni Y, Mechoulam R (1964) Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1646–1647Google Scholar
- Hill AJ, Weston SE, Jones NA, Smith I, Bevan SA, Williamson EM, Stephens GJ, Williams CM, Whalley BJ (2010) delta-Tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats. Epilepsia 51:1522–1532. doi: 10.1111/j.1528-1167.2010.02523.x PubMedCrossRefGoogle Scholar
- Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, Laezza C, Portella G, Bifulco M, Di Marzo V (2006) Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 318:1375–1387. doi: 10.1124/jpet.106.105247 PubMedCrossRefGoogle Scholar
- Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev 62:588–631. doi: 10.1124/pr.110.003004 PubMedCrossRefGoogle Scholar
- Pertwee RG (2004) The pharmacology and therapeutic potential of cannabidiol. In: Di Marzo V (ed) Cannabinoids. Kluwer Academic/Plenum, New York, p 32Google Scholar
- Syvanen S, Lindhe O, Palner M, Kornum BR, Rahman O, Langstrom B, Knudsen GM, Hammarlund-Udenaes M (2009) Species differences in blood–brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport. Drug Metab Dispos 37:635–643. doi: 10.1124/dmd.108.024745 PubMedCrossRefGoogle Scholar
- Takeuchi H, Yatsugi S, Yamaguchi T (2002) Effect of YM992, a novel antidepressant with selective serotonin re-uptake inhibitory and 5-HT 2A receptor antagonistic activity, on a marble-burying behavior test as an obsessive-compulsive disorder model. Jpn J Pharmacol 90:197–200PubMedCrossRefGoogle Scholar