The In Vitro Pharmacological Evaluation of Tetrahydrocannabivarin (THCV) For Intestinal Inflammatory Conditions
dc.contributor.advisor | Mousseau, Darrell | |
dc.contributor.committeeMember | Weber, Lynn | |
dc.contributor.committeeMember | Laprairie, Robert | |
dc.contributor.committeeMember | Al-Dissi, Ahmad | |
dc.creator | He, Jim | |
dc.date.accessioned | 2022-09-26T21:50:12Z | |
dc.date.available | 2022-09-26T21:50:12Z | |
dc.date.copyright | 2022 | |
dc.date.created | 2022-11 | |
dc.date.issued | 2022-09-26 | |
dc.date.submitted | November 2022 | |
dc.date.updated | 2022-09-26T21:50:12Z | |
dc.description.abstract | The recreational and medicinal use of Cannabis for certain human pathologies has received tremendous attention in recent years. Numerous pre-clinical and clinical findings on the benefits of cannabinoids, the naturally occurring constituents in Cannabis, against epilepsy, neuropathic pain, and gastrointestinal (GI) syndromes have allowed many governmental and research sectors to further investigate their therapeutic potential and adverse effects. Currently, several extensively researched cannabinoids such as tetrahydrocannabinol (THC) and cannabidiol (CBD) have shown to possess therapeutic and pharmacological effects in aiding the treatment of various medical conditions. However, due to a desire to enhance our increasing understanding of the physiochemical and pharmacokinetic (PK) characteristics of THC and CBD, research on certain cannabinoids such as tetrahydrocannabivarin (THCV) has not always been the primary focus. Studies on THCV indicated anti-inflammatory effects in in vitro cell lines and in vivo animal models which compelled us to assess the PK characteristics of THCV. In addition to its PK characteristics, our aim was to evaluate the effects of THCV on how it may affect inflammatory conditions of the GI tract such as inflammatory bowel disease (IBD). We first investigated THCV’s intestinal permeation profile and directly assessed its effects on intestinal barrier integrity with an in vitro Transwell system coupled with human epithelial derived cell line comprised of colorectal adenocarcinoma cells (Caco-2). We then examined its interaction with different plasma proteins in human plasma through its relative bound fraction and the unbound fraction in the blood (fu(b)) by adopting the 3-solvent extraction plasma protein binding technique. Enzyme kinetic analysis was conducted to better understand the contribution of liver to the first-pass metabolism and systemic clearance of THCV using human liver microsomes (HLM). Its in vitro intrinsic clearance (Clint,u) was calculated using the substrate depletion approach and was ranked as to whether it was a low, intermediate or high clearance drug. As a secondary aim, we established a 3-D intestinal organoid (IO) model derived from human inducible pluripotent stem cells (iPSCs) for the preliminary screening of THCV putative anti-inflammatory effects. Collectively, THCV demonstrated limited permeation in the Transwell system with a high degree of non-specific binding to plasticware, relatively higher unbound fraction (fu(b)) compared to the literature, and classified as a high clearance drug indicated by its Clint,u value. Further, THCV showed promising anti-inflammatory effects by upregulating an anti-inflammatory cytokine in the IO system. These studies revealed key PK parameters of THCV that is currently unavailable in the literature while the new IO system was capable of upregulating key pro-inflammatory responses upon lipopolysaccharide (LPS) stimulation, which may bridge the gap between traditional in vitro cell culture and in vivo animal models. | |
dc.format.mimetype | application/pdf | |
dc.identifier.uri | https://hdl.handle.net/10388/14228 | |
dc.language.iso | en | |
dc.subject | Cannabinoids | |
dc.title | The In Vitro Pharmacological Evaluation of Tetrahydrocannabivarin (THCV) For Intestinal Inflammatory Conditions | |
dc.type | Thesis | |
dc.type.material | text | |
thesis.degree.department | Toxicology Centre | |
thesis.degree.discipline | Toxicology | |
thesis.degree.grantor | University of Saskatchewan | |
thesis.degree.level | Masters | |
thesis.degree.name | Master of Science (M.Sc.) |