@article {Weidner275, author = {Lora D. Weidner and King Leung Fung and Pavitra Kannan and Janna K. Moen and Jeyan S. Kumar and Jan Mulder and Robert B. Innis and Michael M. Gottesman and Matthew D. Hall}, title = {Tariquidar Is an Inhibitor and Not a Substrate of Human and Mouse P-glycoprotein}, volume = {44}, number = {2}, pages = {275--282}, year = {2016}, doi = {10.1124/dmd.115.067785}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Since its development, tariquidar (TQR; XR9576; N-[2-[[4-[2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]carbamoyl]-4,5-dimethoxyphenyl]quinoline-3-carboxamide) has been widely regarded as one of the more potent inhibitors of P-glycoprotein (P-gp), an efflux transporter of the ATP-binding cassette (ABC) transporter family. A third-generation inhibitor, TQR exhibits high affinity for P-gp, although it is also a substrate of another ABC transporter, breast cancer resistance protein (BCRP). Recently, several studies have questioned the mechanism by which TQR interfaces with P-gp, suggesting that TQR is a substrate for P-gp instead of a noncompetitive inhibitor. We investigated TQR and its interaction with human and mouse P-gp to determine if TQR is a substrate of P-gp in vitro. To address these questions, we used multiple in vitro transporter assays, including cytotoxicity, flow cytometry, accumulation, ATPase, and transwell assays. A newly generated BCRP cell line was used as a positive control that demonstrates TQR-mediated transport. Based on our results, we conclude that TQR is a potent inhibitor of both human and mouse P-gp and shows no signs of being a substrate at the concentrations tested. These in vitro data further support our position that the in vivo uptake of [11C]TQR into the brain can be explained by its high-affinity binding to P-gp and by it being a substrate of BCRP, followed by amplification of the brain signal by ionic trapping in acidic lysosomes.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/44/2/275}, eprint = {https://dmd.aspetjournals.org/content/44/2/275.full.pdf}, journal = {Drug Metabolism and Disposition} }