PT  - JOURNAL ARTICLE
AU  - Tomoe Fujita
AU  - Kazuhiko Ishihara
AU  - Shuichi Yasuda
AU  - Tomomi Nakamura
AU  - Mika Maeda
AU  - Mami Kobayashi
AU  - Kunihiko Sahashi
AU  - Yasuhiko Ikeda
AU  - Yuji Kumagai
AU  - Masataka Majima
TI  - In Vivo Kinetics of Indoxyl Sulfate in Humans and Its Renal Interaction with Angiotensin-Converting Enzyme Inhibitor Quinapril in Rats
AID  - 10.1124/jpet.111.187732
DP  - 2012 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 626--633
VI  - 341
IP  - 3
4099  - http://jpet.aspetjournals.org/content/341/3/626.short
4100  - http://jpet.aspetjournals.org/content/341/3/626.full
SO  - J Pharmacol Exp Ther2012 Jun 01; 341
AB  - Indoxyl sulfate (IS) is an organic anion uremic toxin that accumulates in patients with chronic kidney disease (CKD). The aims of this study were to examine the kinetic profiles of IS in humans at a steady state after multiple doses of l-Trp, a precursor of IS, and the in vivo interaction of IS with the angiotensin-converting enzyme inhibitor quinapril, whose active metabolite is a substrate of organic anion transporter 3 (OAT3) in rats. First, 12-h kinetics after single doses of Trp (2, 4, and 8 g) were examined in two healthy volunteers. Second, 24-h kinetics after a single dose of 2 g of Trp was studied in six volunteers. Third, 35-h kinetics after single and multiple doses of 2 g of Trp were examined in five volunteers. In anesthetized rats, quinapril or probenecid, an inhibitor of OATs, was given intravenously before IS, and blood and urine samples were taken until 90 min. Trp and IS concentrations were determined by high-performance liquid chromatography. Ultrafiltration was used to measure serum unbound IS concentrations. Renal tubular secretion of IS accounted for more than 90% of its renal clearance in the steady state of serum IS levels after multiple doses in humans. In animals, the serum area under the curve of IS increased in conjunction with a decrease in renal clearances after coadministration of IS with quinapril or probenecid. It is concluded that quinapril may inhibit the urine excretion of IS via OAT3-mediated renal tubular transport in patients with CKD.