Talinolol

Encequidar is a gut-restricted P-glycoprotein inhibitor that is a useful tool molecule to boost the oral bioavailability of P-glycoprotein substrates. In this article, we demonstrate that encequidar has moderate to high clearance and volume of distribution, and low oral bioavailabilities (<10%) in rat, dog, and monkey. We show, in vivo, the ability of encequidar to inhibit gut P-glycoprotein and boost the oral exposures of numerous P-glycoprotein probe substrates by 5- to 20-fold in rat, dog, and monkey. In addition, we show low portal vein levels of encequidar, suggesting that it is an efficient gut P-glycoprotein inhibitor but unlikely to inhibit bile canicular P-glycoprotein. We leverage this gut-restricted nature of encequidar to differentiate between intestinal excretion/secretion mediated by gut P-glycoprotein and biliary elimination mediated by canicular P-glycoprotein without the need for bile duct-cannulated animal studies. We show that encequidar can inhibit intestinal secretion of known P-glycoprotein substrates (paclitaxel, apixaban, and talinolol) in rat and dog. The reduction in the amount of parent in feces, post-intravenous dosing, by encequidar reflects intestinal secretion, whereas the remaining amount of parent in feces in the presence of encequidar reflects biliary elimination. In all cases, renal elimination was unaffected by encequidar. In summary, we demonstrate that encequidar can differentiate between the various disposition pathways-renal, biliary, and intestinal-in animals and provides a quick qualitative estimate of the human disposition pathways. SIGNIFICANCE STATEMENT: Encequidar is a potent, gut-restricted P-glycoprotein (P-gp) inhibitor that boosts oral bioavailability of P-gp substrates in the commonly used nonclinical species of rat, dog, and monkey. Encequidar is a suitable in vivo P-gp inhibitor to determine the main routes of elimination and differentiate between intestinal secretion and biliary elimination of P-gp substrates using intact animal models.