Tetrahydrocannabinol and Its Major Metabolites are Not (or are poor) Substrates and Inhibitors of Human P‐glycoprotein (P‐gp/MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2)

Abstract

Cannabis consumption in the United States is rising. (-)-Δ9-tetrahydrocannabinol (THC) is the primary psychoactive constituent of cannabis. In humans, 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THC-COOH) are psychoactive and non-psychoactive circulating metabolites of THC, respectively. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are ATP-binding cassette (ABC) efflux transporters important in drug disposition. Previous animal studies suggest that THC and its metabolites could be substrates of P-gp and BCRP orthologs in mice and macaques; however, whether these cannabinoids are substrates or inhibitors of human P-gp and BCRP is unknown. Therefore, we performed transwell transport, cellular accumulation, and vesicular transport assays using Madin-Darby canine kidney II (MDCKII) cells or plasma membrane vesicles overexpressing human P-gp or BCRP to determine whether THC, 11-OH-THC or THC-COOH, at pharmacologically relevant concentrations, are substrates or inhibitors of these human ABC transporters. Neither THC nor 11-OH-THC was found to be a substrate or inhibitor of P-gp or BCRP. The efflux ratio of THC-COOH in MDCKII-BCRP cells was 1.6, which was significantly decreased to 1.0 by the BCRP inhibitor Ko143. Likewise, cellular accumulation of THC-COOH was significantly increased 1.6-fold in the presence vs. absence of Ko143. THC-COOH also significantly inhibited BCRP-mediated transport of lucifer yellow, a BCRP substrate; however, THC-COOH was neither a substrate nor an inhibitor of P-gp. Collectively, these results indicate that THC and 11-OH-THC are not substrates or inhibitors (at pharmacologically relevant concentrations) of either P-gp or BCRP. THC-COOH is a weak substrate and inhibitor of BCRP, but not of P-gp. Based on these data we predict that P-gp or BCRP will not modulate the brain/fetal distribution or intestinal absorption of these cannabinoids in humans. In addition, significant in vivo drug interactions between these cannabinoids and P-gp or BCRP inhibitors/inducers are unlikely.