PHARMACOKINETIC AND PHARMACODYNAMIC INTERACTION OF SINGLE ORAL DOSES OF VALSARTAN AND FUROSEMIDE

Objective: Pharmacokinetic and pharmacodynamic interactions between si ngle oral doses of valsartan (160 mg) and furosemide (40 mg) were inve stigated in an open, randomized, three-period crossover study in twelv e healthy male subjects.Methods: A washout period of one week was obse rved between treatments. Pharmacokinetic measurements included plasma concentrations of valsartan and furosemide, and urinary excretion of t he latter. Plasma renin activity (PRA), plasma angiotensin II, blood p ressure, heart rate, as well as urinary water and electrolyte excretio n were determined as pharmacodynamic variables. Efficiency of furosemi de for sodium and water excretion was calculated as the ratio of the m easured pharmacodynamic effect and the urinary excretion of furosemide . Results: Simultaneous administration of valsartan and furosemide did not modify the pharmacokinetics of valsartan. In contrast, C-max, AUC , and urinary excretion of furosemide were significantly reduced follo wing simultaneous treatment with valsartan. Inter- and intra-individua l variability of the pharmacokinetic variables was high for both furos emide and valsartan. PRA and angiotensin II increased, and blood press ure decreased after all treatments. These effects were most pronounced after the combined treatment. The decrease in blood pressure was addi tive, at most, while the increase in PRA and angiotensin II appeared t o exceed simple addition. No relevant effects on heart rate were obser ved. The diuretic effect of furosemide, as assessed by urinary water a nd electrolyte excretion, was unchanged after co-administration of val sartan, despite the lower bioavailability of furosemide after the comb ined treatment.