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

Abstract

Cannabis-based products have experienced notable increases in co-usage alongside tobacco products. Several cannabinoids exhibit inhibition of a number of cytochrome P450 (CYP) and UDP glucuronosyltransferase (UGT) enzymes, but few studies have examined their inhibition of enzymes involved in nicotine metabolism. The goal of the present study was to examine potential drug–drug interactions occurring in the nicotine metabolism pathway perpetrated by cannabidiol (CBD) and its active metabolite, 7-hydroxy-CBD (7-OH-CBD). The inhibitory effects of CBD and 7-OH-CBD were tested in microsomes from HEK293 cells overexpressing individual metabolizing enzymes and from human liver tissue. Assays with overexpressing microsomes demonstrated that CBD and 7-OH-CBD inhibited CYP-mediated nicotine metabolism. Binding-corrected IC50,u values for CBD inhibition of nicotine metabolism to cotinine and nornicotine, and cotinine metabolism to trans-3′-hydroxycotinine (3HC), were 0.27 ± 0.060, 0.23 ± 0.14, and 0.21 ± 0.14 μM, respectively, for CYP2A6; and 0.26 ± 0.17 and 0.029 ± 0.0050 μM for cotinine and nornicotine formation, respectively, for CYP2B6. 7-OH-CBD IC50,u values were 0.45 ± 0.18, 0.16 ± 0.08, and 0.78 ± 0.23 μM for cotinine, nornicotine, and 3HC formation, respectively, for CYP2A6, and 1.2 ± 0.44 and 0.11 ± 0.030 μM for cotinine and nornicotine formation, respectively, for CYP2B6. Similar IC50,u values were observed in HLM. Inhibition (IC50,u = 0.37 ± 0.06 μM) of 3HC to 3HC-glucuronide formation by UGT1A9 was demonstrated by CBD. Significant inhibition of nicotine metabolism pathways by CBD and 7-OH-CBD suggests that cannabinoids may inhibit nicotine metabolism, potentially impacting tobacco addiction and cessation.

Vascularized liver-on-a-chip model to investigate nicotine-induced dysfunction

“…This possible antagonistic effect of simultaneous drug use has not been shown either in vivo or in vitro ; however, it proves to be a point of further interest, as nicotine is mainly a substrate of CYP2A6, not CYP3A4. 73 Previous in vivo studies have found that long term smoking in rats caused inhibited CYP3A1 activity, the rat analog to human CYP3A4; 74,75 however, this effect has not been found in vitro prior to this work, nor has it been shown for short term effects.…”

Evaluation of Cytochrome P450‐Mediated Cannabinoid‐Drug Interactions in Healthy Adult Participants

“…A standalone in vivo study using UGT probes is warranted to corroborate these findings. Third, other enzymes that were inhibited by CBD in vitro (e.g., CYP2A6 and CYP2B6), 12,13,42 and transporters involved in drug disposition need to be evaluated with respect to CBD or Δ9-THC interactions in vivo. Fourth, the cannabis extracts used for the current study were administered 30 minutes prior to the probe drug cocktail.…”

Biochemical and genetic biomarkers associated with nicotine dependence in Mexican smokers

“…53 In contrast, in subjects with deficient CYP2A6 activity, increased levels of nicotine-N′-oxide have been found. 16,18 corresponding decrease in 3HC-O-Gluc formation. 19 In the present study, deficiencies in CYP2A6 activity as measured by the NMR resulted in increased levels of nicotine-N′-oxide and decreased levels of 3HC-O-Gluc, particularly in ND subjects.…”

“…13,14 Nicotine and cotinine are N′-oxidized to produce nicotine-N′-oxide by flavin monooxygenase enzymes (FMO1, FMO2, and FMO3) 15,16 and cotinine oxide by CYP2C19 and CYP2A6, 17 respectively. While CYP2A6 has been suggested to play a role in the formation of 4-hydroxy-4-(3-pyridyl)-bu tanoic acid (HPBA), 18 it is presently unclear whether CYP2A6 is the sole enzyme involved in this pathway (Figure 1). 19 and the levels of 3HC-O-Gluc (p < .0001, r = .6835), while a strong negative correlation was observed with nicotine-N′-oxide (p < .0001, r = .6522) in nicotine-dependent subjects.…”