Cannabinoid Metabolites as Inhibitors of Major Hepatic CYP450 Enzymes, with Implications for Cannabis-Drug Interactions

Abstract

The legalization of cannabis in many parts of the United States and other countries has led to a need for a more comprehensive understanding of cannabis constituents and their potential for drug-drug interactions. Although (−)- trans -Δ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are the most abundant cannabinoids present in cannabis, THC metabolites are found in plasma at higher concentrations and for a longer duration than that of the parent cannabinoids. To understand the potential for drug-drug interactions, the inhibition potential of major cannabinoids and their metabolites on major hepatic cytochrome P450 (P450) enzymes was examined. In vitro assays with P450-overexpressing cell microsomes demonstrated that the major THC metabolites 11-hydroxy-Δ 9 -tetra-hydrocannabinol and 11-nor-9-carboxy-Δ 9 -THC-glucuronide competitively inhibited several major P450 enzymes, including CYP2B6, CYP2C9, and CYP2D6 (apparent K i,u values = 0.086 ± 0.066 µM and 0.90 ± 0.54 µM, 0.057 ± 0.044 µM and 2.1 ± 0.81 µM, 0.15 ± 0.067 µM and 2.3 ± 0.54 µM, respectively). 11-Nor-9-carboxy-Δ 9 - tetrahydrocannabinol exhibited no inhibitory activity against any CYP450 tested. THC competitively inhibited CYP1A2, CYP2B6, CYP2C9, and CYP2D6; CBD competitively inhibited CYP3A4, CYP2B6, CYP2C9, CYP2D6, and CYP2E1; and CBN competitively inhibited CYP2B6, CYP2C9, and CYP2E1. THC and CBD showed mixed-type inhibition for CYP2C19 and CYP1A2, respectively. These data suggest that cannabinoids and major THC metabolites are able to inhibit the activities of multiple P450 enzymes, and basic static modeling of these data suggest the possibility of pharmacokinetic interactions between these cannabinoids and xenobiotics extensively metabolized by CYP2B6, CYP2C9, and CYP2D6. SIGNIFICANCE STATEMENT Major cannabinoids and their metabolites found in the plasma of cannabis users inhibit several P450 enzymes, including CYP2B6, CYP2C9, and CYP2D6. This study is the first to show the inhibition potential of the most abundant plasma cannabinoid metabolite, THC-COO-Gluc, and suggests that circulating metabolites of cannabinoids play an essential role in CYP450 enzyme inhibition as well as drug-drug interactions.

Clinical Relevance of Drug Interactions with Cannabis: A Systematic Review

“… a The recommendations for the management of each interaction are according to the level of the clinical relevance of cannabis–drug interactions [ 8 , 9 , 10 ]. In addition, some information stated by the authors was included.…”

“…Cannabinoids, especially CBD, are metabolized by isoenzymes of the family CYP, which can lead to interactions between a cannabis base extract and other drugs. In this way, recent in vitro studies have shown that: THC competitively inhibits the enzymes CYP1A2, CYP2B6, CYP2C9, and CYP2D6; CBD competitively inhibits the enzymes CYP3A4, CYP2B6, CYP2C9, CYP2D6, and CYP2E1; and cannabinol (CBN) competitively inhibits the enzymes CYP2B6, CYP2C9, and CYP2E1 [ 9 ]. By contrast, drug interactions due to pharmacodynamic mechanisms are generally less common [ 6 ].…”

Herb–Drug Interaction in Inflammatory Diseases: Review of Phytomedicine and Herbal Supplements

“…Duloxetine (several drugs in other fields; propofol, anticoagulants!) in vitro: inhibition of several CYP enzymes by cannabinoids and main metabolites, including CYP 2B6, 2C9, 2D6; minor inhibition: 1A2, 2C19, 3A4 [60,62] Several drugs, including opioids, NSAIDs and possibly cyclosporine and tacrolimus (CBD) [63] anticholinergic agents (risk of tachycardia) (several drugs in other fields)…”

“…Cannabinoids are substrates of CYP3A4 and 2C9. In vitro data suggest the influence of cannabinoids and their metabolites on several CYP 450 enzymes [ 62 , 124 ]. The strongest effects were CYP2C9, 2B6, and 2D6 inhibition, but CYP 1A2, 2C19, and 3A4 might be affected as well.…”

Considerations for Cannabinoids in Perioperative Care by Anesthesiologists

“…Cannabinoid Cannabinoid Effect Anesthetic CYP2B6 THC, CBD THC and CBD both are inhibitors [300] Propofol [301], Ketamine [302,303] CYP2C9 THC, Cannabinol [304] THC as inhibitor [300,305] Propofol [301], Ketamine [302,303], Rocuronium [306] CYP2E1 THC metabolites, CBD Competetive inhibition [300] Halothane [307], Isoflurane [307], Sevoflurane [307], Enflurane [307], Desflurane [307,308] CYP3A4 THC, CBD, Cannabinol CBD is an inhibitor [300,309] Ketamine [302], Midazolam [310], Diazepam [311], Fentanyl [312], Rocuronium [306], Codeine [307,313], Propofol [301], Acetaminophen [314] CYP2A6 THC Genotype-dependent [295] Dexmedetomidine [315] CYP2C19 THC, CBD THC and CBD are both inhibitors [309] Diazepam [311], Rocuronium [306] CYP1A1/2 CBD CBD is an inducer [309] Diazepam [311] CYP2D6 THC, CBD THC and CBD are both inhibitors [300] Tramadol [316], Codeine [314,317], Oxycodone [314,318], Hydrocodone…”