PT  - JOURNAL ARTICLE
AU  - Zhu, Hao-Jie
AU  - Wang, Jun-Sheng
AU  - Markowitz, John S.
AU  - Donovan, Jennifer L.
AU  - Gibson, Bryan B.
AU  - Gefroh, Holly A.
AU  - DeVane, C. Lindsay
TI  - Characterization of P-glycoprotein Inhibition by Major Cannabinoids from Marijuana
AID  - 10.1124/jpet.105.098541
DP  - 2006 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 850--857
VI  - 317
IP  - 2
4099  - http://jpet.aspetjournals.org/content/317/2/850.short
4100  - http://jpet.aspetjournals.org/content/317/2/850.full
SO  - J Pharmacol Exp Ther2006 May 01; 317
AB  - 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: Δ9-tetrahydrocannabinol (THC), 11-nor-Δ9-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 (Vmax/Km) 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. The American Society for Pharmacology and Experimental Therapeutics