D-Malate decreases renal content of [alpha]-ketoglutarate, a driving force of organic anion transporters OAT1 and OAT3, resulting in inhibited tubular secretion of phenolsulfonphthalein, in rats

• Published in: Biopharmaceutics & drug disposition Vol. 38; no. 8; p. 479
• Main Authors: Uwai, Yuichi, Kawasaki, Tatsuya, Nabekura, Tomohiro
• Format: Journal Article
• Language: English
• Published: Bognor Regis Wiley Subscription Services, Inc 01.11.2017
• Subjects: Creatinine; Excretion; Intravenous administration; Ions; Ketoglutaric acid; Kidneys; Krebs cycle; Rats; Reabsorption; Renal cortex; Renal function; Rodents; Secretion; Tricarboxylic acid cycle; Urine
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.2089

d-Malate inhibits a Krebs cycle enzyme and the tubular transport of [alpha]-ketoglutarate, an intermediate of the Krebs cycle and the driving force for rat organic anion transporter 1 (rOAT1) and rOAT3 in the kidney. This study examined the effects of d-malate on the rat organic anion transport system. The uptake of 6-carboxyfluorescein by HEK293 cells expressing rOAT1 or rOAT3 was not affected by d-malate and l-malate. Up to 60 min after the intravenous injection of phenolsulfonphthalein (PSP), a typical substrate of the renal organic anion transporters, as a bolus to rats, 47.1% of the dose was recovered in the urine, and its renal clearance was estimated to be 8.60 ml/min/kg. d-Malate but not l-malate interfered with its renal excretion, resulting in the delayed elimination of PSP from plasma. No effect of d-malate was recognized on creatinine clearance or the expression level of rOAT3 in the kidney cortex. d-Malate increased the plasma concentration of [alpha]-ketoglutarate. In addition, the compound greatly stimulated the renal excretion of [alpha]-ketoglutarate, implying that d-malate inhibited its reabsorption. The content of [alpha]-ketoglutarate was significantly decreased in the kidney cortex of rats administered d-malate. Collectively, this study shows that d-malate abrogates the tubular secretion of PSP, and the reduction of the renal content of [alpha]-ketoglutarate was proposed to be one of the mechanisms. A relationship between the reabsorption of [alpha]-ketoglutarate and the basolateral uptake of organic anion in the kidney is suggested.