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.

Does the Adequacy Parameter Kt/Vurea Reflect Uremic Toxin Concentrations in Hemodialysis Patients?

“…These include renal tubular secretion (IS, HA) [52] , metabolic factors (ADMA) [53] , intestinal secretion, absorption and generation (UA) [54] , (indoles, phenols) [29] , [55] , [56] , (IS) [57] , [58] . [26] , [59] , [60] . Impressive differences in serum concentration of different solutes, either adjusted or not for Kt/V urea , were found in our present study (ranging from 72 to close to 100%), confirming previous data in another hemodialyzed population (concentration differences ranging from 66 to 100%) [26] , so that the same interfering factors may also play an as important role in dialysis patients as in non-dialyzed CKD patients.…”

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

“…Microbial toxins might act as competitive inhibitors of OAT tubular secretion of both endogenous solutes and drugs, and vice versa, thereby increasing systemic exposure. For example, OAT1 and OAT3 mediated tubular secretion of indoxyl sulfate is competitively inhibited by non-steroidal anti-inflammatory drugs (NSAIDs), quinapril and probenecid [76,77], which may increase systemic exposure of drugs and/or indoxyl sulfate. Indoxyl sulfate, CMPF and hippuric acid also have inhibitory effects on OAT1 and OAT3 activity [78–80].…”

Analysis of membrane transport mechanisms of endogenous substrates using chromatographic techniques

“…Indoxyl sulfate is a well‐known uremic toxin that interacts with organic anion transporters. Transport by SLC22A6, SLC22A8 and SLCO1B3 was determined using RP‐HPLC–UV (Enomoto et al, ), RP‐HPLC–FL (Fujita et al, ) and LC/ESI–MS/MS (Sato et al, ), respectively. From these studies, it is suggested that indoxyl sulfate is a substrate for not only renal transporters SLC22A6 and SLC22A8 but also hepatic transporter SLCO1B3.…”