Cited by 192Drug Transport and Resistance MechanismsCannabis and Cannabinoid ResearchPharmacogenetics and Drug Metabolism

Characterization of P-glycoprotein Inhibition by Major Cannabinoids from Marijuana

Zhu, Hao-Jie, Wang, Jun-Sheng, Markowitz, John S., Donovan, Jennifer L., Gibson, Bryan B., Gefroh, Holly A., DeVane, C. Lindsay·2006·The Journal of Pharmacology and Experimental Therapeutics

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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Crossref · 10.1124/jpet.105.098541

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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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