In Vivo Kinetics of Indoxyl Sulfate in Humans and Its Renal Interaction with Angiotensin-Converting Enzyme Inhibitor Quinapril in Rats

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.

硫酸吲哚酚（IS）是一种有机阴离子尿毒症毒素，在慢性肾脏病（CKD）患者体内蓄积。本研究的目的是检测多次给予IS的前体L - 色氨酸（L - Trp）后人体处于稳态时IS的动力学特征，以及IS与血管紧张素转换酶抑制剂喹那普利在体内的相互作用，喹那普利的活性代谢产物在大鼠中是有机阴离子转运体3（OAT3）的底物。首先，在两名健康志愿者中检测单次给予色氨酸（2克、4克和8克）后的12小时动力学。其次，在六名志愿者中研究单次给予2克色氨酸后的24小时动力学。第三，在五名志愿者中检测单次和多次给予2克色氨酸后的35小时动力学。在麻醉大鼠中，在给予IS之前静脉注射喹那普利或丙磺舒（一种OATs抑制剂），并采集血液和尿液样本直至90分钟。色氨酸和IS的浓度通过高效液相色谱法测定。采用超滤法测量血清中未结合的IS浓度。在人体多次给药后血清IS水平达到稳态时，IS的肾小管分泌占其肾清除率的90%以上。在动物中，IS与喹那普利或丙磺舒共同给药后，IS的血清曲线下面积增加，同时肾清除率降低。结论是，在CKD患者中，喹那普利可能通过OAT3介导的肾小管转运抑制IS的尿排泄。