Cannabis L. (Cannabis sativa)
Characterization of P-glycoprotein Inhibition by Major Cannabinoids from Marijuana CSV JSON

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.

1 . CBD-Rh123 (Flow-Cytometry Assay) (id=NPDI-pvvgAw)

In Vitro Transporter Inhibition Experiment

Inhibition was detected.  Cutoff used —

Inhibition of Rh123 efflux caused by the treatment of 5 μM PSC833 was defined as 100% inhibition

Rhodamine 123

cannabidiol (CBD)

  • P-gp (ABCB1)

Transfected / siRNA knock-out / injected cells LLC-PK1 transfected cells

Results

Accumulation estimated from Fig 3a at 30 μM of CBD. p < 0.01 versus control
%inhibition estimated from Fig 5 at 100 μM.
IC50 found within text

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Cell Culture Conditions

1x10^5 cells/mL/well

Assay Conditions

60 m

37'C

7.4

5 µM

2, 5, 10, 20, 50, 100 µM

Sigma-Aldrich (St. Louis, MO)