A105: Extent and duration of angiotensin ii antagonistic activity of irbesartan and candesartan cilexetil

Objective: Previous results indicate that within the class of angiotensin II, AT1 receptor antagonists, irbesartan (IRB) and candesartan cilexetil (CAN) exhibit a longer duration of angiotensin II (ANG II) antagonism than do losartan (LOS) and valsartan (VAL) (Malerczyk C et al.: Br J Clin Pharmacol 1998;45:567–573; Belz GG et al.: Clin Pharmacol Ther 1999;66:367–373). The aim of this study was to directly compare the antagonistic activity of IRB 150 mg and CAN 8 mg assessed in vivo and in vitro in man. Methods: Eighteen healthy male volunteers were enrolled in a double-blind, randomized, cross-over study. Responses to exogenous ANG II and a radioligand rat lung receptor assay (RRA) were performed before and up to 47 h after single (day 1) and multiple (day 8) oral dosing. The rightward shift (DR-1) of ANG II dose effect curves assessed the effects in vivo and the concentration equivalents (n × Ki) from plasma assessed the effects in vitro. Results: Both IRB and CAN showed a similar degree of antagonistic activity in vivo with some time delay (tmax) following CAN administration. Clear antagonistic effects even at 47 h after the last dose were found with IRB and CAN (mean DR-1 of 1.28 IRB, 1.45 CAN) and both substances demonstrated a similar decline of effect after 10 h (left Figure). However, distinctly higher concentration equivalents from plasma ex vivo/in vitro were seen in RRA following IRB at all timepoints (right figure). Conclusions: The extent and duration of ANG II antagonistic properties in vivo of IRB 150 mg and CAN 8 mg were similar. IRB demonstrated a distinctly higher ex vivo/in vitro antagonistic activity in plasma.