DUP-532, AN ANGIOTENSIN-II RECEPTOR ANTAGONIST - FIRST ADMINISTRATIONAND COMPARISON WITH LOSARTAN

We investigated the tolerability and angiotensin II antagonist activit y of oral DuP 532 in healthy male subjects. DuP 532 (1 to 200 mg) was well tolerated, with no effect on blood pressure or heart rate. Compar ed with losartan (100 mg), DuP 532 (200 mg) was a weak antagonist of p resser responses to intravenous angiotensin II. Maximum inhibition of diastolic presser response was 86% (95% confidence interval [CI], 84%, 88%) approximately 4.6 hours after losartan and 48% (95% CI, 38%, 56% ) 8.7 hours after Dull 532. Twenty-four hours after dosing, inhibition by losartan and DuP 532 was similar (40% to 45%). DUP 532 is extensiv ely bound in human plasma, with an in vitro free fraction of 0.06. Alt hough DuP 532 and EXP3174 (losartan's active metabolite) have similar AT(1)-receptor potency, and plasma concentrations of DuP 532 were much greater than losartan/EXP3l74, the level of antagonism was much less for DuP 532. These results indicate that multiple factors determine th e in vivo potency of angiotensin II antagonists, including affinity fo r and distribution to the receptor as modulated by plasma binding.