SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria

Biopharm Drug Dispos. 2014 Oct;35(7):391-404. doi: 10.1002/bdd.1909. Epub 2014 Aug 6.

Abstract

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.

Keywords: GLUT9; SGLT2 inhibitor; sodium glucose cotransporter; uric acid; urinary glucose excretion.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Animals
  • Biological Transport / drug effects
  • Biological Transport / physiology
  • Biomarkers / blood
  • Dose-Response Relationship, Drug
  • Female
  • Glucose / toxicity
  • Glycosuria / chemically induced
  • Glycosuria / metabolism*
  • Humans
  • Kidney Tubules / drug effects
  • Kidney Tubules / metabolism*
  • Male
  • Sodium-Glucose Transporter 2 / metabolism*
  • Sodium-Glucose Transporter 2 Inhibitors*
  • Sorbitol / analogs & derivatives*
  • Sorbitol / pharmacology
  • Uric Acid / blood*
  • Xenopus laevis
  • Young Adult

Substances

  • Biomarkers
  • SLC5A2 protein, human
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Uric Acid
  • Sorbitol
  • 1,5-anhydro-1-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)-1-thioglucitol
  • Glucose