Glucose transporter 9 inhibition as a potential novel approach for lowering uric acid.

Glucose transporter 9 (GLUT9) is a uric acid transporter that plays a key role in maintaining uric acid homeostasis. JTT-763 is a novel GLUT9 inhibitor identified based on its uric acid transport inhibitory activity against human GLUT9 (hGLUT9). Using JTT-763 as a pharmacological tool, we aimed to evaluate the concept of GLUT9 inhibition for urate lowering. In vitro, JTT-763 inhibited uric acid transport by hGLUT9 short form (hGLUT9S) and hGLUT9 long form (hGLUT9L) in a concentration-dependent manner and showed high selectivity for hGLUT9 over other uric acid-related molecules. JTT-763 also inhibited uric acid transport through hGLUT9S/L co-expressing cells, a model that mimics renal uric acid reabsorption in vivo. In mice, JTT-763 increased uric acid excretion in urine but did not significantly affect blood uric acid levels. Therefore, we evaluated JTT-763 in tufted capuchin monkeys, whose uric acid metabolism is relatively similar to humans. JTT-763 showed a significant dose-dependent decrease in blood uric acid levels, and this effect was stronger than that of benzbromarone, an existing uricosuric drug, on a dose basis. Unexpectedly, benzbromarone significantly increased urinary uric acid excretion in monkeys, whereas JTT-763 did not. These results suggest that GLUT9 inhibition increases uric acid excretion not only in the kidney but also from extrarenal tissues and may represent a novel urate-lowering approach for hyperuricemia.