Predicting the Potential of Major Cannabinoids and Their Metabolites to Precipitate Cytochrome P450‐mediated Drug Interactions

Abstract

Background Cannabis products are used for recreational and medicinal purposes. The major cannabinoids, cannabidiol (CBD) and tetrahydrocannabinol (THC), are inhibitors of several cytochromes P450 (CYPs). However, their low aqueous solubility and significant binding to human liver microsomes (HLM)/proteins or labware have not been considered. Moreover, CYP inhibition by their circulating metabolites, 7-OH CBD/7-COOH CBD and 11-OH THC/11-COOH THC, has not been evaluated. We hypothesized that the inhibitory potencies of CBD and THC and their potential to precipitate CYP-mediated drug interactions have been underestimated. Objectives Our objective was to assess potential CYP-mediated cannabinoid-drug interactions using an IVIVE approach. The aims were to determine the following for each cannabinoid and metabolite: 1) binding to HLM proteins, labware, and plasma; 2) unbound reversible CYP inhibitory potency (IC50,u); and 3) unbound time-dependent CYP inhibition (TDI) potency (KI,u) and apparent maximum inactivation rate constant (kinact,app). These data were used to predict the magnitude of cannabinoid-drug interactions for oral or inhaled doses used for recreational or medicinal purposes. Methods Fraction unbound of CBD, THC, or metabolite in incubations containing HLM and BSA (fu,inc) or plasma (fu,p) was determined by ultracentrifugation. IC50,u,KI,u, andkinact,app were estimated by assessing the effect of varying concentrations of CBD, THC, or metabolite on the formation of CYP-mediated metabolites of phenacetin (CYP1A2), coumarin (CYP2A6), bupropion (CYP2B6), amodiaquine (CYP2C8), diclofenac (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and testosterone (CYP3A) using HLM. These data, along with expected intestinal and unbound hepatic inlet (oral dose) or systemic plasma (inhaled dose) concentrations, were used to predict the potential for interactions between typical doses of CBD (700 mg) or THC (20 mg) and drugs predominantly metabolized by these enzymes. Results fu,inc of CBD, 7-OH CBD, and THC was 0.03, 0.02, and 0.13, respectively; corresponding fu,p was 0.01, 0.02, and 0.01. CBD or THC inhibited all the tested CYPs (IC50,u < 0.68 μM). Comparatively, 7-OH CBD or 11-OH THC were less potent inhibitors (IC50,u < 5.3 μM). Both CBD and 7-OH CBD showed TDI of CYP2C19 and CYP3A; CBD showed TDI of CYP1A2. A mechanistic static model predicted in vivo interactions (AUC ratio > 1.4) between CBD and drugs significantly metabolized by CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A. Oral THC was predicted to interact with drugs metabolized by CYP2C9 and 3A (AUC ratio > 1.7), whereas inhaled THC is unlikely to interact with these drugs. CYP inhibition by CBD or THC metabolites had no effect on the predicted magnitude of CBD- or THC-drug interactions. Conclusion This study is the first to consider binding of CBD, THC, and metabolites to microsomal protein and labware to estimate CYP inhibition potential. A clinical study is ongoing to verify our static model predictions of cannabinoid-drug interactions.