Characterization of P-glycoprotein Inhibition by Major Cannabinoids from Marijuana
Abstract
The ATP-dependent drug efflux transporter P-glycoprotein (P-gp) plays a significant role in the absorption and disposition of many compounds. The purpose of this study was to investigate the possible interaction of P-gp with each of four major marijuana constituents: Delta(9)-tetrahydrocannabinol (THC), 11-nor-Delta(9)-tetrahydrocannabinol-carboxylic acid (THC-COOH), cannabinol (CBN), and cannabidiol (CBD). The results of a P-gp ATPase activity screen showed that THC-COOH, CBN, THC, and CBD all stimulated P-gp ATPase activity with a Michaelis-Menten parameter (V(max)/K(m)) value of 1.3, 0.7, 0.1, and 0.05, respectively. Furthermore, CBD showed a concentration-dependent inhibitory effect on verapamil-stimulated ATPase activity with an IC(50) value of 39.6 microM, whereas all other tested cannabinoids did not display appreciable inhibitory effects. Thus, the inhibitory effects of CBD on P-gp transport were further studied. At concentrations ranging from 5 to 100 microM, CBD robustly enhanced the intracellular accumulation of known P-gp substrates rhodamine 123 and doxorubicin in a concentration-dependent manner in Caco-2 and LLC-PK1/MDR1 cells. An IC(50) value of 8.44 microM was obtained for inhibition of P-gp function in LLC-PK1/MDR1 cells as determined by flow cytometry using rhodamine 123 as a fluorescence probe. Following exposure to 30 microM CBD, the apparent permeability coefficient of rhodamine 123 across Caco-2 and rat brain microvessel endothelial cell monolayers was increased to 2.2- and 2.6-fold in the apical-to-basolateral direction but decreased to 0.69- and 0.47-fold in the basolateral-to-apical direction, respectively. These findings indicate that CBD significantly inhibits P-gp-mediated drug transport, suggesting CBD could potentially influence the absorption and disposition of other coadministered compounds that are P-gp substrates.
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Preclinical studies have reported that cannabinoids may also bind membrane transporters including breast cancer resistance protein and P-gp, which can, theoretically, impact the effect of other medications.
“Preclinical studies have reported that cannabinoids may also bind membrane transporters including breast cancer resistance protein111 and P-gp,112,113 which can, theoretically, impact the effect of other medications.”
From Clinical Practice Guidelines for Cannabis and Cannabinoid-Based Medicines in the Management of Chronic Pain and Co-Occurring Conditions (2024) · cites this paper as [113]
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“110 Preclinical studies have reported that cannabinoids may also bind membrane transporters including breast cancer resistance protein 111 and P-gp, 112,113 which can, theoretically, impact the effect of other medications.”
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- Authors
- Zhu, H.-J., Wang, J.-S., Markowitz, J. S., Donovan, J. L., Gibson, B. B., Gefroh, H. A., & DeVane, C. L.
- Affiliations
- Medical University of South Carolina (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2006-05
- Volume
- 317
- Issue
- 2
- Pages
- 850-857
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2160246128
- Cited by
- 192
- References
- 39
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 15 · 2023: 15 · 2022: 14 · 2021: 16 · 2020: 18 · 2019: 13 · 2018: 11 · 2017: 5 · 2016: 11 · 2015: 11 · 2014: 5 · 2013: 7 · 2012: 6
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- P-glycoprotein, P-glycoprotein inhibition, cannabidiol, cannabinoids, cannabis, delta-9-tetrahydrocannabinol, THC-COOH, cannabinol, verapamil, rhodamine 123, doxorubicin, intestinal permeability, brain microvascular endothelial cells, Caco-2 cells, drug transport, drug-drug interactions
- MeSH terms
- Adenosine Triphosphatases, Animals, Biological Transport, Cannabinoids, Cannabis, Cell Line, Dose-Response Relationship, Drug, Humans, Verapamil, ATP Binding Cassette Transporter, Subfamily B, Member 1, Endothelial Cells, Rats
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