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 C(max) and AUCO-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 C(max) and AUCO-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.