Torasemide transport by organic anion transporters contributes to Hyperuricemia

The high renal clearance of torasemide, the most potent loop diuretic, suggests active tubular secretion in the proximal tubule. Previous studies implicated the organic anion transporters (OAT) in this process; human OAT1 (hOAT1) and hOAT3 are found on the basolateral surface of proximal tubule cells, and hOAT4 is found on the luminal surface. This study sought to determine the mechanism underlying renal elimination of torasemide and to elucidate the drug's effect on renal urate secretion, because hyperuricemia is a concerning adverse effect. Torasemide and its metabolites were transported into stably transfected HEK293 cells by hOAT1, hOAT3, and hOAT4 and out of the cells by hOAT3 and hOAT4. These data suggest that basolateral hOAT3 and luminal hOAT4 are likely responsible for the translocation of torasemide across the proximal tubule cell. Regarding urate handling, torasemide and its metabolites did not interact with human URAT1, but competitive inhibition of the basolateral OAT for urate may reduce tubular secretion. Furthermore, because hOAT4 can reabsorb urate from the urinary lumen, increased urate reabsorption may occur as exchange for the secretion of torasemide and its metabolites. In support of this hypothesis, fractional excretion of urate was reduced in 95 healthy volunteers after torasemide administration. In summary, this study determined the affinity of OAT for torasemide and its metabolites and proposed a mechanism underlying torasemide-induced hyperuricemia that does not involve the human URAT1-mediated transport affected by other loop diuretics.