Itoh N, Sawada Y, Sugiyama Y, Iga T, Hanano M
Am J Physiol. 1986 Jul;251(1 Pt 2):F103-14. doi: 10.1152/ajprenal.1986.251.1.F103.
New methods, based on the multiple-indicator dilution (MID) technique, to study the kinetic relations between the renal tubular cell entry process and the secretory process of drugs are proposed. [3H]Cimetidine was used as a model drug. T-1824-labeled albumin (a vascular reference), [14C]creatinine (an extracellular reference), and [3H]cimetidine were rapidly injected into the renal artery of isolated perfused rat kidney, and normalized outflow-time patterns were secured from rapidly sampled renal venous perfusate. A distributed two-compartment model was fitted to the dilution data by nonlinear least-squares regression, and the influx, efflux, and sequestration rate constants were estimated. Both the influx and the sequestration process (based on the unbound cimetidine concentration) had two transport systems (i.e., Michaelis-Menten-type saturable transport and linear-type passive transport), whereas the efflux process was independent of the intracellular cimetidine concentration. At the low dose of cimetidine the influx clearance was larger than those of the efflux and sequestration, whereas at the high dose no remarkable difference was observed among these three clearances due to the large decrease in the influx clearance. Thus the MID technique is a sensitive new method to study the rate-limited process of renal tubular transport in rats.
提出了基于多指示剂稀释（MID）技术的新方法，用于研究肾小管细胞摄取过程与药物分泌过程之间的动力学关系。以西咪替丁[3H]作为模型药物。将T-1824标记的白蛋白（一种血管标志物）、[14C]肌酐（一种细胞外标志物）和西咪替丁[3H]快速注入离体灌注大鼠肾脏的肾动脉，并从快速采集的肾静脉灌注液中获取标准化的流出时间模式。通过非线性最小二乘回归将分布二室模型拟合到稀释数据中，并估算流入、流出和滞留速率常数。流入和滞留过程（基于未结合的西咪替丁浓度）均具有两个转运系统（即米氏型饱和转运和线性型被动转运），而流出过程与细胞内西咪替丁浓度无关。在低剂量西咪替丁时，流入清除率大于流出和滞留清除率，而在高剂量时，由于流入清除率大幅下降，这三种清除率之间未观察到显著差异。因此，MID技术是研究大鼠肾小管转运限速过程的一种灵敏的新方法。
