Dissertation
POTENTIAL INTERACTIONS OF CANNABINOIDS AND THEIR METABOLITES ON MAJOR DRUG METABOLIZING ENZYMES: IMPLICATION ON CO-USE OF TOBACCO AND CANNABIS
Washington State University
Doctor of Philosophy (PhD), Washington State University
01/2022
DOI:
https://doi.org/10.7273/000004405
Handle:
https://hdl.handle.net/2376/123550
Abstract
Cannabis-based products have seen increased usage in many parts of the world and in the US, including increases in co-usage with tobacco products. This has led to a need for a more comprehensive understanding of cannabis constituents and their potential for cannabis-drug interactions (CDI) as well as cannabis-tobacco interactions (CTI). While (−)-trans-Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are major cannabinoids present in cannabis, the THC metabolites 11-hydroxy-∆9-tetra-hydrocannabinol (11-OH-THC), 11-COO-Δ9-THC (THC-COOH), and 11-COO-Δ9-THC-glucuronide (THC-COO-Gluc) are found in plasma at higher concentrations than cannabinoids in cannabis users. To better understand the potential for CDI and CTI, the inhibitory potential of cannabinoids and metabolites on Phase I [(cytochrome P450 (CYP)] and Phase II [UDP-glucuronosyltransferase (UGT)] enzymes and on the nicotine metabolism pathway were investigated. In vitro assays demonstrated that the major THC metabolites 11-OH-THC and THC-COO-Gluc competitively inhibited CYP2B6, CYP2C9, and CYP2D6. Basic static modeling populated with these data were indicative of the possibility of pharmacokinetic interactions in vivo. Major UGTs were also inhibited by cannabinoids, though no inhibition was observed by THC metabolites. The highest inhibition was observed for CBD against UGTs 1A9, 2B4,1A6, and 2B7.. Potent inhibition of UGT1A9 and UGT2B7 was also demonstrated by THC and CBN. Significant inhibition of nicotine metabolism pathways by CBD and 7-OH-CBD was also observed. CBD and 7-OH-CBD inhibited nicotine metabolism to cotinine and nornicotine in CYP2A6 and CYP2B6-overexpressing microsomes, cotinine metabolism to trans-3’-hydroxycotinine (3HC) in CYP2A6 overexpressing microsomes, and 3HC to 3HC-glucuronide in UGT1A9-overexpressing microsomes. The findings presented in this dissertation suggest that circulating cannabinoids and their metabolites may be inhibiting major CYP and UGT enzymes in users of cannabis products, potentially resulting in CDIs. In addition, cannabinoids like CBD and 7-OH-CBD inhibit nicotine metabolism, potentially decreasing the desire to smoke more cigarettes in smokers who are co-users of cannabis products due to higher endogenous nicotine levels, suggesting that cannabinoids could be important as smoking cessation agents. These findings will help clinicians and researchers identify prescription medications that may have adverse effects when combined with cannabis products.
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Details
- Title
- POTENTIAL INTERACTIONS OF CANNABINOIDS AND THEIR METABOLITES ON MAJOR DRUG METABOLIZING ENZYMES
- Creators
- Shamema Nasrin
- Contributors
- Philip Lazarus (Advisor)Bhagwat Prasad (Committee Member)Senthil Natesan (Committee Member)Gang Chen (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 217
- Identifiers
- OCLC#: 1365112523; 99900883237801842
- Language
- English
- Resource Type
- Dissertation