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­­­­­­Cannabinoid metabolites as inhibitors of major hepatic CYP450 enzymes, with implications for cannabis-drug interactions

Shamema Nasrin, Christy J.W. Watson, Yadira X Perez-Paramo and Philip Lazarus
Drug Metabolism and Disposition September 7, 2021, DMD-AR-2021-000442; DOI: https://doi.org/10.1124/dmd.121.000442
Shamema Nasrin
1Washington state university, United States
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Christy J.W. Watson
2Pharmaceutical Sciences, Washington State University, United States
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Yadira X Perez-Paramo
3OMNI-Biomarker Development, Genentech Inc., United States
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Philip Lazarus
4Pharmaceutical Sciences, Washington State University College of Pharmacy, United States
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  • For correspondence: phil.lazarus@wsu.edu
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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. While (−)-trans-Δ⁹-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 (CYP) enzymes was examined. In vitro assays with CYP-overexpressing cell microsomes demonstrated that the major THC metabolites 11-hydroxy-∆9-tetra-hydrocannabinol (11-OH-THC) and 11-COO-Δ9-THC-glucuronide (THC-COO-Gluc) competitively inhibited several major CYP enzymes, including CYP2B6, CYP2C9, and CYP2D6 (apparent Ki,u values = 0.086 {plus minus} 0.066 µM and 0.90 {plus minus} 0.54 µM, 0.057 {plus minus} 0.044 µM and 2.1{plus minus} 0.81 µM, 0.15 {plus minus} 0.067 µM and 2.3 {plus minus} 0.54 µM, respectively). 11-nor-9-carboxy-Δ9- tetrahydrocannabinol (THC-COOH) exhibited no inhibitory activity against any CYP450 tested. THC competitively inhibited CYPs 1A2, 2B6, 2C9, and 2D6, CBD competitively inhibited CYPs 3A4, 2B6, 2C9, 2D6, and 2E1, and CBN competitively inhibited CYPs 2B6, 2C9, and 2E1. 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 CYP enzymes, and basic static modelling 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 CYP 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.

  • cannabinoids
  • CYP inhibition
  • CYP2B
  • CYP2C9
  • CYP2D6
  • Cytochrome P450 (CYP)
  • drug metabolism
  • drug-drug interactions
  • enzyme inhibitors
  • © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.
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Drug Metabolism and Disposition: 51 (2)
Drug Metabolism and Disposition
Vol. 51, Issue 2
1 Feb 2023
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Cannabinoid metabolites as CYP450 inhibitors

Shamema Nasrin, Christy J.W. Watson, Yadira X Perez-Paramo and Philip Lazarus
Drug Metabolism and Disposition September 7, 2021, DMD-AR-2021-000442; DOI: https://doi.org/10.1124/dmd.121.000442

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Cannabinoid metabolites as CYP450 inhibitors

Shamema Nasrin, Christy J.W. Watson, Yadira X Perez-Paramo and Philip Lazarus
Drug Metabolism and Disposition September 7, 2021, DMD-AR-2021-000442; DOI: https://doi.org/10.1124/dmd.121.000442
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