Diuresis by intravenous administration of xanthurenic acid in rats, and inhibition by probenecid

Abstract

The conjugates with sulfate and glucoside of xanthurenic acid, a tryptophan metabolite, were reported to show natriuresis. Sulfotransferase for xanthurenic acid works in the renal proximal tubule to produce the sulfate of xanthurenic acid as well as the liver, and we recently found that xanthurenic acid is a substrate of renal organic anion transporter OAT1. The purpose of this study was to examine relationship between the transport by OAT1 and diuresis related with xanthurenic acid. Drug transport experiment using Xenopus laevis oocytes represented that probenecid inhibited xanthurenic acid uptake by rat OAT1 (rOAT1). Although no diuresis was recognized by the intravenous injection of xanthurenic acid as a bolus in rats, the addition of its infusion exhibited natriuresis. Simultaneous administration of probenecid significantly decreased the urine volume and excreted amounts of sodium into urine. These findings showed the diuresis by the xanthurenic acid administration, and it was probenecid-sensitive. The rOAT1-mediated transport of xanthurenic acid might, at least in part, contribute to its diuretic effect.In the renal proximal tubules, organic anion transporters secrete endogenous metabolites, drugs, and xenobiotics into urine. From the mid-1990s, cDNA of renal organic anion transporters has been isolated, and its function and expression have been characterized. Organic anion transporters OAT1 and OAT3 are thought to be responsible for the renal tubular uptake of organic anions from blood, and multidrug resistance-associated protein MRP4 is the strong candidate mediating their efflux into lumen (2). Our laboratory has been interested in transport of bioactive substances by OAT1 and OAT3. Recently, we examined interaction of the metabolites of the kynurenine pathway, a main route for the tryptophan metabolism, with OAT1 and OAT3, and represented that kynurenic acid and xanthurenic acid were transported by them (5, 6). Kynurenic acid antagonizes N-methyl D-aspartate (NMDA) receptor in the brain under physiological conditions, and is accepted as the key molecule in several psychiatric disorders (3). Xanthurenic acid is closely structurally related to kynurenic acid (Fig.