title: 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.
abstract: BACKGROUND
  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), Δ(9)-tetrahydrocannabivarin (Δ(9)-THCV) and cannabigerol (CBG).
  
  
  OBJECTIVE
  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.
  
  
  RESULTS
  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 Δ(9)-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
authors.forename: Serena
authors.initials: S
authors.lastname: Deiana
authors.forename: Akihito
authors.initials: A
authors.lastname: Watanabe
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: Naoki
authors.initials: N
authors.lastname: Amada
authors.forename: Marlene
authors.initials: M
authors.lastname: Arthur
authors.forename: Shona
authors.initials: S
authors.lastname: Fleming
authors.forename: Hilary
authors.initials: H
authors.lastname: Woodcock
authors.forename: Patricia
authors.initials: P
authors.lastname: Dorward
authors.forename: Barbara
authors.initials: B
authors.lastname: Pigliacampo
authors.forename: Steve
authors.initials: S
authors.lastname: Close
authors.forename: Bettina
authors.initials: B
authors.lastname: Platt
authors.forename: Gernot
authors.initials: G
authors.lastname: Riedel
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002185:Cannabidiol / Q000097:blood* / Q000493:pharmacokinetics; D002186:Cannabinoids / Q000097:blood* / Q000493:pharmacokinetics; D003192:Compulsive Behavior / Q000097:blood* / Q000188:drug therapy; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D009770:Obsessive Behavior / Q000097:blood* / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002186:Cannabinoids; D002185:Cannabidiol; C003403:tetrahydrocannabivarin 9; D013759:Dronabinol; C037036:cannabigerol