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 n ine patients with essential hypertension. Participants were given plac ebo 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-ho ur blood pressure was measured on days -1, 1, and 7 and blood samples for measurement of losartan and its active metabolite, E-3174, were ob tained on days 1 and 7. Plasma concentrations of uric acid and plasma clearance were determined before and during treatment with losartan, a nd at the end of the study. Pharmacokinetic parameters after the seven th dose, including maximum plasma concentration (C-max) and time to C- max (t(max)) of losartan and E-3174, did not differ significantly from those after the first dose. The blood pressure lowering effect of los artan, however, was significantly greater after the seventh dose than after the first dose. Plasma uric acid decreased and its plasma cleara nce (Cl-UA) increased significantly during repeated administration wit h 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 adminis tration, the blood pressure lowering effect in hypertensive patients i s greater after multiple doses than after a single dose.