Kinetic analysis of rat renal tubular transport based on multiple-indicator dilution method

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.