Preclinical Pharmacokinetic Studies of a Novel Diuretic Inhibiting Urea Transporters.

Urea transporter (UT) inhibitors are a class of promising novel diuretics that do not cause the imbalance of Na, K, Cl, and other electrolytes. In our previous studies, , a promising diuretic candidate inhibiting UT, was discovered and showed potent diuretic activities in rodents. Here, a sensitive liquid chromatography-tandem mass spectrometry method for the quantitation of in rat plasma, urine, feces, bile, and tissue homogenates was developed and validated to support the preclinical pharmacokinetic studies. The tissue distribution, excretion, and plasma protein binding were investigated in rats. After a single oral dose of at 25, 50, and 100 mg/kg, the drug exposure increased linearly with the dose. The drug accumulation was observed after multiple oral doses compared to a single dose. In the distribution study, exhibited a wide distribution to tissues with high blood perfusion, such as kidney, heart, lung, and spleen, and the lowest distribution in the brain and testis. The accumulative excretion rate of was 0.14%, 3.16%, and 0.018% in urine, feces, and bile, respectively. The plasma protein binding of was approximately 60% in rats and 40% in humans. This is the first study on the preclinical pharmacokinetic profiles of .