THE EFFECTS OF N-BENZOYL-BETA-ALANINE, A NEW NEPHROPROTECTIVE DRUG, ON THE DISTRIBUTION AND RENAL EXCRETION OF ENPROFYLLINE IN RATS

The effects of the new nephroprotective drug N-benzoyl-beta-alanine (B A) on the disposition and renal excretion of the bronchodilator enprof ylline, which is actively secreted in urine, were investigated in rats . Enprofylline was administered intravenously at a dosage of 2.5 mg kg -1 under three different steady-state plasma BA concentrations (100, 2 00 and 400 mug mL-1) which were achieved by constant infusion rates. P harmacokinetic parameters for both total and unbound enprofylline were estimated by model-independent methods. The presence of BA (400 mug m L-1) increased the systemic clearance by 25% and the volume of distrib ution at steady-state by 90%. A significant increase in the dissociati on constant, which is the protein binding parameter of enprofylline wa s observed in the presence of BA (400 mug mL-1), indicating that BA co mpetitively inhibits the protein binding of enprofylline. However, BA significantly decreased the systemic clearance and volume of distribut ion for unbound enprofylline. These results suggest that BA, the organ ic anion transport inhibitor, inhibits renal excretion of enprofylline with a high affinity for renal tubular secretion, although the unboun d concentration of enprofylline increases with administration of BA. W e conclude that BA decreases the renal tubular secretion of enprofylli ne probably by reducing the affinity of the tubular transport system, and that these changes have marked effects on the pharmacokinetic beha viour of enprofylline.