Cannabinoid metabolites as potential inhibitors of major CYP450 enzymes. Implication for cannabis‐drug interactions.

Abstract

The recent legalization of marijuana in many parts of the United States and other countries has led to an increased need for a more comprehensive understanding of the metabolism of marijuana constituents, specifically in regard to potential drug‐drug interactions (DDIs) with cannabinoids and their numerous metabolites. To understand the DDI potential of cannabis, we are evaluating cannabis constituents and cannabinoid metabolites as possible inhibitors of phase I metabolizing enzymes. We hypothesize that inhibition of major drug metabolizing enzymes by cannabinoids metabolites [(−)‐trans‐Δ‐9‐ tetrahydrocannabinol (THC), 11‐hydroxy Δ9‐tetra hydrocannabinol(11‐OH‐THC), 11‐nor‐9‐carboxy‐Δ9‐tetrahydrocannbinol (THC‐COOH), THC‐COO‐glucuronide, cannabidiol (CBD) and cannabinol (CBN] can lead to an increase in hepatic and systemic exposure to certain drugs. In vitro assays demonstrated that THC, its major metabolites 11‐OH‐THC, THC‐COOH and THC‐COO‐glucuronide, CBD and CBN inhibit several major CYP enzymes. THC (IC50= 10 ± 4.7 μM), 11‐OH‐THC (IC50= 2.8 ± 1.4 μM), THC‐COO‐glucuronide (IC50= 7.6 ± 4.8 μM), and CBD (2.8 ± 1.2 μM) all inhibited the dextromethorphan‐O‐demethylase activity of recombinant CYP2D6. THC (IC50= 8.3 ± 3.2 μM), THC‐COO‐glucuronide (IC50= 7.2 ± 4.1 μM), CBD (IC50= 8.1 ± 4.3 μM) and CBN (IC50= 5.5 ± 3.1 μM) all inhibited the omeprazole‐5‐hydroxylase activity of recombinant CYP2C19, while 11‐OH‐THC (IC50= 5.02 ± 2.3 μM), THC‐COO‐glucuronide (IC50= 5.2 μM ± 3.5 μM), CBD (IC50= 0.8 ± 0.5 μM), and CBN (IC50= 1.5 ± 0.9 μM) all inhibited the bupropion hydroxylation activity of recombinant CYP2B6. In addition, CBD and CBN inhibited the chlorzoxazone‐6‐hydroxylase activity of recombinant CYP2E1 (IC50 were 0.9 μM ± 0.5 μM and 0.6 μM ± 0.4 μM, respectively). These data indicate that cannabinoids and their major metabolites are able to inhibit the activities of multiple CYP enzymes, suggesting a strong possibility for DDI with many exogenous compounds including a variety of drugs and carcinogens.Support or Funding InformationThis investigation was supported in part by funds provided by the State of Washington Initiative Measure No. 502