The clinical pharmacology of losartan in Japanese subjects and patients.

The pharmacokinetics and biochemical efficacy of losartan, an orally active nonpeptide angiotensin II (A II)-receptor antagonist, were studied in healthy male volunteers after single oral dose administration and multiple oral dose Administration and found that the long-lasting blocking effect ofLosartan on A II action can be attributed to the plasma levels of its active metabolite, E-3174.

Abstract

The pharmacokinetics and biochemical efficacy of losartan, an orally active nonpeptide angiotensin II (A II)-receptor antagonist, were studied in healthy male volunteers after single oral dose administration (25, 50, 100, or 200 mg) and multiple oral dose administration (100 mg or placebo once a day for 7 days). Plasma and urinary concentrations of losartan and its active metabolite, E-3174, were determined. The mean Cmax and area under the curve (AUC) values increased in a dose-dependent manner. The terminal half-life of losartan ranged from 1.5 to 2.5 hours. Plasma concentration of E-3174 was higher than that of losartan at all dose levels. The Cmax and AUC values for E-3174 were approximately two and five to eight times higher than those for losartan, respectively. Furthermore, the half-life of E-3174 was two times that of losartan. After multiple dosing for 7 days, the pharmacokinetics of losartan or E-3174 did not change significantly between day 1 and day 7. Plasma renin activity and plasma concentration of A II increased at all dose levels. Plasma aldosterone levels were slightly reduced, but a similar decrease was also observed with placebo. The urinary excretion of uric acid within the first 4 hours after treatment was also increased in a dose-dependent manner, whereas the urinary excretion of creatinine remained unchanged. In other pharmacokinetic studies, it has been reported that bioavailability of losartan is about 33%, and its absorption is excellent. The metabolite is excreted via urine and the bile. Based on our observations, the half-life and plasma concentrations of E-3174 were greater than those of losartan. In conclusion, the long-lasting blocking effect of losartan on A II action can be attributed to the plasma levels of its active metabolite, E-3174.