Physiologically based pharmacokinetic model for the renal clearance of salicyluric acid and the interaction with phenolsulfonphthalein in the dog

Abstract

Plasma kinetics and renal excretion of salicyluric acid (SUA, 0.8 g) administered iv, with and without concomitant administration of phenolsulfonphthalein (PSP), were studied in the beagle dog. Pharmacokinetic analysis revealed that tubular secretion is the predominant route of excretion, and that secretion is inhibited by PSP. A physiologically based kidney model is presented comprising all the functional characteristics of the kidney that determine the excretion of SUA, i.e. renal plasma flow, urine flow, nonlinear protein binding, glomerular filtration, tubular secretion, and tubular accumulation. The model enabled an accurate description and analysis of the measured plasma levels and renal excretion rates. The interaction with PSP could be adequately described with the model by noncompetitive inhibition of the carrier-mediated uptake of SUA into the tubular cells. Furthermore, a small but significant reduction in nonrenal SUA clearance was observed. Model calculations showed that, in the control experiments, tubular secretion was accompanied by a pronounced accumulation of SUA within the cells, which was clearly diminished in the presence of PSP. The predicted accumulation ratios were in good agreement with previously reported in vitro values.