Sodium glucose cotransporter 2 (
SGLT2) inhibitors have been reported to lower the serum
uric acid (SUA) level. To elucidate the mechanism responsible for this reduction, SUA and the urinary excretion rate of
uric acid (UE(UA)) were analysed after the
oral administration of
luseogliflozin, a
SGLT2 inhibitor, to healthy subjects. After dosing, SUA decreased, and a negative correlation was observed between the SUA level and the UE(UA), suggesting that SUA decreased as a result of the increase in the UE(UA). The increase in UE(UA) was correlated with an increase in urinary
D-glucose excretion, but not with the plasma
luseogliflozin concentration. Additionally, in vitro transport experiments showed that
luseogliflozin had no direct effect on the transporters involved in renal UA reabsorption. To explain that the increase in UE(UA) is likely due to
glycosuria, the study focused on the facilitative
glucose transporter 9
isoform 2 (GLUT9ΔN, SLC2A9b), which is expressed at the apical membrane of the kidney tubular cells and transports both UA and
D-glucose. It was observed that the efflux of [(14) C]UA in Xenopus oocytes expressing the GLUT9
isoform 2 was trans-stimulated by 10 mm
D-glucose, a high concentration of
glucose that existed under SGLT2 inhibition. On the other hand, the uptake of [(14) C]UA by oocytes was cis-inhibited by 100 mm
D-glucose, a concentration assumed to exist in collecting ducts. In conclusion, it was demonstrated that the UE(UA) could potentially be increased by
luseogliflozin-induced
glycosuria, with alterations of UA transport activity because of urinary
glucose.