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Understanding the Cytochrome P450‐Catalyzed Metabolism of Cannabidiol and the Implications for Hepatotoxicity
Author(s) -
Beers Jessica,
Fu Dong,
Jackson Klarissa
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03121
Subject(s) - cannabidiol , cyp2c19 , pharmacology , metabolite , cyp3a4 , cytochrome p450 , dravet syndrome , cyp3a , chemistry , drug metabolism , cyp2b6 , microsome , metabolism , biochemistry , enzyme , drug , medicine , cannabis , epilepsy , psychiatry
Cannabidiol (CBD) is a naturally occurring, non‐psychotoxic phytocannabinoid that has gained public attention for its use as an active ingredient in many consumer products and for its recent FDA approval as Epidiolex® (CBD oral solution) in treating seizures associated with Lennox‐Gastaut syndrome and Dravet syndrome. Epidiolex® has been associated with dose‐dependent hepatotoxicity in clinical trials, and the risk is increased when Epidiolex® is given with valproate, another anti‐epileptic drug known to cause liver injury. The mechanism of CBD‐related hepatotoxicity, however, remains unknown. CBD is metabolized primarily by cytochrome P450 (CYP) 2C19 and CYP3A4, and by UDP‐glucuronosyltransferases (UGTs) to a lesser extent. The goals of this study were to characterize the roles of CYP enzymes in the metabolism of CBD with a focus on generation of the active metabolite 7‐hydroxy‐CBD (7‐OH‐CBD) and major inactive metabolite 7‐carboxy‐CBD (7‐COOH‐CBD), and to investigate the impact of CYP2C19 genotype on CBD metabolism in human liver microsomes (HLM). We also examined the effect of co‐treatment with the nonselective CYP inhibitor 1‐aminobenzotriazole and valproate on CBD metabolite generation in sandwich‐cultured human hepatocytes (SCHH). Reaction phenotyping experiments using recombinant enzymes and HLM treated with CYP‐selective chemical inhibitors indicated that CYP2C19 can sequentially metabolize CBD to 7‐OH‐CBD and 7‐COOH‐CBD. Although CYP3A was found to have a significant role in overall CBD clearance and 7‐COOH‐CBD formation, CYP3A was not involved in 7‐OH‐CBD generation. In addition, HLM from CYP2C19 poor metabolizers were found to have significantly higher 7‐COOH‐CBD generation compared to CYP2C19 rapid and ultrarapid metabolizers. In SCHH pre‐treated with 1‐aminobenzotriazole, formation of hydroxylated CBD metabolites was reduced, while CBD‐glucuronide formation increased. Co‐treatment with CBD and valproate in SCHH did not significantly alter the metabolic profile of CBD. Further work is needed to determine the mechanisms of CBD‐related hepatotoxicity and the interaction between CBD and valproate.