title: In vivo kinetics of indoxyl sulfate in humans and its renal interaction with angiotensin-converting enzyme inhibitor quinapril in rats.
abstract: 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.
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami, Sagamihara, Kanagawa 252-0374, Japan. fujita-t@kitasato-u.ac.jp
authors.forename: Tomoe
authors.initials: T
authors.lastname: Fujita
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Ishihara
authors.forename: Shuichi
authors.initials: S
authors.lastname: Yasuda
authors.forename: Tomomi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Mika
authors.initials: M
authors.lastname: Maeda
authors.forename: Mami
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Sahashi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D006801:Humans; D007200:Indican / Q000652:urine*; D007668:Kidney / Q000187:drug effects*; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D007677:Kidney Function Tests; D008297:Male; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology; D000077583:Quinapril; D051381:Rats; D044005:Tetrahydroisoquinolines / Q000493:pharmacokinetics*; D014118:Toxins, Biological / Q000378:metabolism; D055815:Young Adult
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D029362:Organic Anion Transporters, Sodium-Independent; D044005:Tetrahydroisoquinolines; D014118:Toxins, Biological; C114338:organic anion transport protein 3; D007200:Indican; D011339:Probenecid; D000077583:Quinapril