Clinical pharmacology of multiple-dose losartan, an angiotensin II receptor antagonist, in patients with essential hypertension.

The pharmacokinetic and pharmacodynamic alterations of multiple doses of losartan, an angiotensin II receptor antagonist, were examined in nine patients with essential hypertension. Participants were given placebo once daily for the first 7 days (from day -7 to day -1), and then 50 mg of losartan for the next 9 days (from day 1 to day 9). The 24-hour blood pressure was measured on days -1, 1, and 7 and blood samples for measurement of losartan and its active metabolite, E-3174, were obtained on days 1 and 7. Plasma concentrations of uric acid and plasma clearance were determined before and during treatment with losartan, and at the end of the study. Pharmacokinetic parameters after the seventh dose, including maximum plasma concentration (Cmax) and time to Cmax (tmax) of losartan and E-3174, did not differ significantly from those after the first dose. The blood pressure lowering effect of losartan, however, was significantly greater after the seventh dose than after the first dose. Plasma uric acid decreased and its plasma clearance (ClUA) increased significantly during repeated administration with losartan. These values returned to pretreatment levels after the end of treatment. These results suggest that although the pharmacokinetic profiles of losartan and E-3174 do not change during repeated administration, the blood pressure lowering effect in hypertensive patients is greater after multiple doses than after a single dose.

RCT Entities:   Population Interventions Outcomes