Received for publication November 14, 2005.
Revised January 24, 2006.
Accepted for publication January 25, 2006.

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: ⁹-tetrahydrocannabinol(THC); 11-Nor-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 IC₅₀ value of 39.6 µM, while 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 5µM to 100µM, CBD robustly enhanced the intracellular accumulation of known P-gp substrates rhodamine123 and doxorubicin in a concentration dependent manner in Caco-2 and LLC-PK1/MDR1 cells. An IC₅₀ value of 8.44 µM was obtained for inhibition of P-gp function in LLC-PK1/MDR1 cells as determined by flow cytometry using rhodamine123 as a fluorescence probe. Following exposure to 30 µM CBD, the apparent permeability coefficient of rhodamine123 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.

Key words: P-glycoprotein, absorption, cannabidiol, cannabinoids, disposition, transport

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