Organic Anion Transporter 1 Is Inhibited by Multiple Mechanisms and Shows a Transport Mode Independent of Exchange

• DOI: 10.1124/dmd.115.065748
• Publication Date: 2015-09-15T01:43:13Z
• Authors: Adam G. Hotchkiss; Tiandai Gao; Usman Khan; Liam Berrigan; Mansong Li; Leslie Ingraham; Ryan M. Pelis
• Keywords: Telmisartan; Efflux

The mechanism by which drugs inhibit organic anion transporter 1 (OAT1) was examined. OAT1 stably expressed in Chinese hamster ovary (CHO) cells, and <i>para</i>-aminohippurate (PAH) 6-carboxyfluorescein were the substrates. Most compounds (10 of 14) inhibited competitively, increasing Michaelis constant (<i>K</i>_m) without affecting maximal transport rate (<i>J</i>_max). Others mixed-type (lowering <i>J</i>_max <i>K</i>_m) or noncompetitive only) inhibitors. interaction a inhibitor (telmisartan) with examined further. Binding telmisartan to observed, but translocation not. Telmisartan did not alter plasma membrane expression OAT1, indicating that it lowers reducing turnover number. PAH after treatment its washout recovered faster presence 10% fetal bovine serum buffer, binding inhibitory effect are reversible. Together, these data suggest binds reversibly site distinct from substrate stabilizes conformation unfavorable for translocation. In absence an exchangeable extracellular substrate, efflux CHO-OAT1 cells relatively rapid. slowed efflux, suggesting some transporter-mediated occurs independent exchange. Although drug-drug predictions at assume competitive inhibition, show can be other mechanisms, could influence accuracy transporter. useful examining how activity uncovering mode