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SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria
Author(s) -
Chino Yukihiro,
Samukawa Yoshishige,
Sakai Soichi,
Nakai Yasuhiro,
Yamaguchi Junichi,
Nakanishi Takeo,
Tamai Ikumi
Publication year - 2014
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.1909
Subject(s) - glycosuria , chemistry , endocrinology , medicine , renal glucose reabsorption , uric acid , cotransporter , reabsorption , hypouricemia , excretion , renal physiology , glucose transporter , kidney , renal function , biochemistry , sodium , insulin , diabetes mellitus , type 2 diabetes , organic chemistry
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 m m 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 m m 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. © 2014 The Authors. Biopharmaceutics & Drug Disposition . Published by John Wiley & Sons Ltd.