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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Characterization of P-glycoprotein Inhibition by Major Cannabinoids from Marijuana

Laboratory of Drug Disposition and Pharmacogenetics, Departments of Pharmaceutical Sciences (H.-J.Z., J.S.M.) and Psychiatry and Behavioral Sciences (J.-S.W., J.L.D., B.B.G., H.A.G., C.L.D.), Medical University of South Carolina, Charleston, South Carolina

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 mari-juana 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, 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 µM, 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 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 rhodamine 123 as a fluorescence probe. Following exposure to 30 µM 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.

Address correspondence to: Dr. C. Lindsay DeVane, Laboratory of Drug Disposition and Pharmacogenetics, Medical University of South Carolina, 173 Ashley Ave., Rm 405B, Charleston, SC 29425. E-mail: devanel{at}musc.edu

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