TY - JOUR T1 - Tariquidar Is an Inhibitor and Not a Substrate of Human and Mouse P-glycoprotein JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 275 LP - 282 DO - 10.1124/dmd.115.067785 VL - 44 IS - 2 AU - Lora D. Weidner AU - King Leung Fung AU - Pavitra Kannan AU - Janna K. Moen AU - Jeyan S. Kumar AU - Jan Mulder AU - Robert B. Innis AU - Michael M. Gottesman AU - Matthew D. Hall Y1 - 2016/02/01 UR - http://dmd.aspetjournals.org/content/44/2/275.abstract N2 - 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. ER -