title: 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: 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.
authors.affiliation: Laboratory of Drug Disposition and Pharmacogenetics, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Hao-Jie
authors.initials: HJ
authors.lastname: Zhu
authors.forename: Jun-Sheng
authors.initials: JS
authors.lastname: Wang
authors.forename: John S
authors.initials: JS
authors.lastname: Markowitz
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Donovan
authors.forename: Bryan B
authors.initials: BB
authors.lastname: Gibson
authors.forename: Holly A
authors.initials: HA
authors.lastname: Gefroh
authors.forename: C Lindsay
authors.initials: CL
authors.lastname: Devane
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002186:Cannabinoids / Q000302:isolation & purification / Q000494:pharmacology*; D002188:Cannabis / Q000737:chemistry*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051381:Rats; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002186:Cannabinoids; D014700:Verapamil; D000251:Adenosine Triphosphatases