Understanding the Cytochrome P450‐Catalyzed Metabolism of Cannabidiol and the Implications for Hepatotoxicity

Abstract

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.