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Drug Metab Dispos. 2021 Jul 29:DMD-AR-2021-000505. doi: 10.1124/dmd.121.000505. On-line forward of print.
(-)-Δ9-tetrahydrocannabinol (THC) is the first psychoactive constituent of hashish. In people, 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THC-COOH) are psychoactive and non-psychoactive circulating metabolites of THC, respectively. Whether or not these cannabinoids are substrates or inhibitors of human P-glycoprotein (P-gp) or breast most cancers resistance protein (BCRP) is unknown. Earlier animal research counsel that THC and its metabolites could possibly be substrates of those transporters. Subsequently, we carried out Transwell, mobile accumulation, and vesicular transport assays, at pharmacologically related concentrations of those cannabinoids, utilizing Madin-Darby canine kidney II (MDCKII) cells or plasma membrane vesicles overexpressing human P-gp or BCRP. Neither THC nor 11-OH-THC was discovered 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 considerably decreased to 1.0 by the BCRP inhibitor Ko143. Likewise, mobile accumulation of THC-COOH was considerably elevated 1.6-fold within the presence vs. absence of Ko143. THC-COOH additionally considerably inhibited BCRP-mediated transport of lucifer yellow, a BCRP substrate; nevertheless, THC-COOH was neither a substrate nor an inhibitor of P-gp. Collectively, these outcomes point out that THC and 11-OH-THC will not be substrates or inhibitors (at pharmacologically related concentrations) of both P-gp or BCRP. THC-COOH is a weak substrate and inhibitor of BCRP, however not of P-gp. Accordingly, we predict that P-gp/BCRP won’t modulate the disposition of those cannabinoids in people. As well as, use of those cannabinoids won’t lead to P-gp- or BCRP-based drug interactions. Significance Assertion On this research, we systematically investigated whether or not THC and its main metabolites 11-OH-THC and THC-COOH are substrates and/or inhibitors of human P-gp and BCRP at pharmacologically related concentrations. The outcomes obtained are extremely invaluable for mechanistic understanding and prediction of the roles of P-gp and BCRP in figuring out the human pharmacokinetics, tissue distribution, and drug interactions of cannabinoids.