Cytochrome P450–Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol

Abstract

Cannabidiol (CBD) is a naturally occurring, non-psycho-toxic phytocannabinoid that has gained increasing attention as a popular consumer product and for its use in FDA-approved Epidiolex® (CBD oral solution) for the treatment of Lennox-Gastaut syndrome and Dravet syndrome. CBD was previously reported to be metabolized primarily by cytochrome P450 (CYP) 2C19 and CYP3A4, with minor contributions from UDP-glucuronosyltransferases. 7-Hydroxy-CBD (7-OH-CBD) is the primary active metabolite with equipotent activity compared to CBD. Given the polymorphic nature of CYP2C19, we hypothesized that variable CYP2C19 expression may lead to interindividual differences in CBD metabolism to 7-OH-CBD. The objectives of this study were to further characterize the roles of CYP enzymes in CBD metabolism, specifically to the active metabolite 7-OH-CBD, and to investigate the impact of CYP2C19 polymorphism on CBD metabolism in genotyped human liver microsomes. The results from reaction phenotyping experiments with recombinant CYP enzymes and CYP-selective chemical inhibitors indicated that both CYP2C19 and CYP2C9 are capable of CBD metabolism to 7-OH-CBD. CYP3A played a major role in CBD metabolic clearance via oxidation at sites other than the 7-position. In genotyped human liver microsomes, 7-OH-CBD formation was positively correlated with CYP2C19 activity but was not associated with CYP2C19 genotype. In a subset of single-donor human liver microsomes with moderate to low CYP2C19 activity, CYP2C9 inhibition significantly reduced 7-OH-CBD formation, suggesting that CYP2C9 may play a greater role in CBD 7hydroxylation than previously thought. Collectively, these data indicate that both CYP2C19 and CYP2C9 are important contributors in CBD metabolism to the active metabolite 7-OH-CBD.

Pharmacovigilance on cannabidiol as an antiepileptic agent

“…Multiple aspects of CBD pharmacology are associated with drug interactions potentially linked to its use with other medications, in particular with those able to influence CYP450 isoenzyme activity (Manikandan et al, 2018;Foster et al, 2019). In fact, CBD is an inhibitor of CYP450 enzymes such as CYP3A4 and CYP2C19 (Beers et al, 2021). To a lesser extent, CBD also has an inhibitory effect on the activity of CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP3A5, CYP2D6, CYP2C9, and on the glucuronidation enzymes UGT1A9 and UGT2B7 (Qian et al, 2019).…”

Contemplating cannabis? The complex relationship between cannabinoids and hepatic metabolism resulting in the potential for drug-drug interactions

“…Cannabidiol is metabolized extensively by the CYP450 system ( 13 , 15 , 17 , 18 ), primarily by hydroxylation ( 21 ); while not all research agrees on the specific enzymes involved in CBD metabolism, it is clear that many are implicated. In addition to the CYP2C9, CYP2C19, CYP3A4, UGT1A9, and UGT2B7 enzymes involved in general cannabinoid metabolism ( 18 ), CYP2C8, CYP1A2, and CYP2B6 are also potentially implicated in CBD metabolism; several additional studies suggest that CYP2C9, CYP2C19, and CYP3A4 likely play the greatest role in metabolism of CBD ( 21 , 33 , 34 ).…”

Inhibition of Nicotine Metabolism by Cannabidiol (CBD) and 7-Hydroxycannabidiol (7-OH-CBD)

“…CBD metabolism to its major active metabolite, 7-hydroxy-CBD (7-OH-CBD), and its subsequent inactive metabolite, 7-carboxy-CBD (CBD-COOH), is mediated by cytochromes P450 (CYPs) 2C9, 2C19, and 3A4 . While the pharmacology of 7-OH-CBD is not well studied, 7-OH-CBD exhibits a t 1/2 that is longer than that of CBD and is found in the plasma of CBD users.…”