Pharmacokinetic and pharmacodynamic studies of piretanide in rabbits. II: Effects on the proximal tubules and the loop of Henle.

In order to clarify the effect of piretanide in the nephrons, pharmacokinetics and pharmacodynamics of piretanide were studied under a hydropenic condition in the rabbit. The hydropenic condition was developed by a simultaneous infusion of an antidiuretic hormone and hyperosmotic saline. Lithium was used as the indicator of the proximal sodium reabsorption. Plasma concentrations and urinary excretion rates of piretanide were not influenced by the hydration state of the body. The glomerular filtration rate (GFR) showed a long lasting decrease after piretanide administration; however, the urinary excretion rates of salts and water were increased prominently just after administration. The lithium clearance ratio, which was obtained by dividing the lithium renal clearance by GFR, indicated that piretanide inhibited the proximal reabsorption of sodium. The urine osmolarity after piretanide administration showed a significant decrease, and this indicated that the osmolarity of the renal medulla was also influenced by piretanide. From these observations, a model describing the transport of water and osmotic substances in the nephrons was constructed to calculate the effect of piretanide. The results indicated that the diuretic effect of piretanide in the hydropenic rabbit was reasonably described by the model. The model parameters obtained suggested that the site of action of piretanide in the proximal tubules might be in the peritubular side rather than inside the lumen, whereas the site of action in the loop of Henle might be inside the lumen.