Pharmacokinetics and biochemical efficacy after single and multiple oral administration of losartan, an orally active nonpeptide angiotensin II receptor antagonist, in humans.

1. The pharmacokinetics and biochemical efficacy of losartan, an orally active nonpeptide angiotensin II (AII) receptor antagonist, were evaluated in healthy male volunteers after single and multiple oral administration. 2. Plasma and urinary concentrations of losartan and its active metabolite, E-3174, were determined by a specific high performance liquid chromatographic (h.p.l.c.) method. 3. Plasma concentrations of losartan were proportional to dose over the range of 25 to 200 mg and the terminal half-lives (t1/2,z) ranged from 1.5 to 2.5 h. The mean values of Cmax and AUC0-infinity increased in a dose-dependent manner. 4. Plasma concentrations of E-3174 were higher than those of losartan at all dose levels. The values of Cmax and AUC0-infinity for E-3174 were approximately 2 and 5-8 times higher than those for losartan, respectively. Also the value of t1/2,z was 2 times longer than that of losartan. 5. After multiple dosing for 7 days, the pharmacokinetics of losartan and E-3174 each did not change significantly between day 1 and day 7. 6. Plasma renin activity (PRA) and plasma concentrations of AII increased markedly at all dose levels. Plasma aldosterone levels were slightly reduced, but a similar decrease was also observed with placebo. 7. No clinically significant adverse reaction was observed in any of the volunteers during either study. Blood counts, routine laboratory tests, urine analyses, and electrocardiograms were also not modified by losartan. 8. Losartan appears to be a potent orally active angiotensin II antagonist with a relatively long duration of action.