The In Vitro Pharmacology of Cannabidivarin (CBDV)
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Cannabis and the family of cannabinoids were first popularized due to the psychoactive profile elicited by a major cannabinoid, Δ9-tetrahydrocannabinol (THC). In recent decades, the rejuvenation and rapid increase in popularity of cannabinoid research arose due to another major cannabinoid, cannabidiol (CBD), and its therapeutic potential in inflammation, neurological disorders, and many other diseases. However, to standardize the medical and recreational use of Cannabis, the lesser-known cannabinoids including cannabidivarin (CBDV) also require pharmacokinetic (PK) and pharmacodynamic (PD) evaluations. While CBD and CBDV are similar in structure and other aspects, such as therapeutic potential as an anti-epileptic and anti-inflammatory agent, a complete understanding of the pharmacological profile for CBDV is lacking. The aim of this thesis was to perform PK and PD evaluations of CBDV utilizing various in vitro methods for two purposes: 1) to support current and future literature, and 2) to present alternatives to animal and human testing. First, the plasma protein binding characteristics of CBDV in human pooled plasma was studied using a three-solvent extraction protocol, allowing for the prediction of the unbound fraction as well as the binding fractions of CBDV to various plasma proteins. Next, the metabolic stability of CBDV was assessed via the substrate depletion method and the linear extrapolation stability assay with human liver microsomes to determine in vitro intrinsic clearance. Intestinal permeability was determined via a Transwell® system comprised of human colorectal adenocarcinoma cell (Caco-2), a model of the intestinal epithelium; however, due to lack of CBDV detection in the receiver compartments of the Transwell®, limitations of the current gold-star method were examined instead. In terms of PD assessment, human induced pluripotent stem cells (iPSCs) were cultured and used to grow brain organoids, which are multi-cellular and self-organizing three-dimensional aggregates capable of mimicking the human brain. The brain organoids exposed to an inflammatory stimulus were used for the preliminary screening of anti-inflammatory potential of CBDV. These studies revealed that plasma protein binding of CBDV was determined to be not clinically significant due to the highly unbound fraction (> 20%); however, CBDV is a high clearance drug due to its high unbound intrinsic clearance value (> 100.0 µL/min/mg). Brain organoids, in response to lipopolysaccharide (LPS) stimulation, revealed potential anti-inflammatory effects with CBDV treatment. Our data suggests these studies are valuable assets capable of determining in vitro human PK parameters of CBDV, which are currently understudied and unreported, as is its role in the inflammatory response. This thesis provides the groundwork for future studies and demonstrates that in vitro models could be a useful tool to compare with traditional in vivo methods.
DegreeMaster of Science (M.Sc.)
SupervisorAlcorn, Jane; Mousseau, Darrell D
CommitteeHowland, John; Chicoine, Al; Blakley, Barry