Comparative Pharmacodynamics and Pharmacokinetics of Candesartan and Losartan in Man

Abstract

The angiotensin II antagonistic effects of candesartan and losartan were compared in-vivo after single and repeated doses. Effects were related to antagonistic activity in plasma. In this double-blind, crossover study, 12 healthy male volunteers received, in random order, daily oral doses of 8 mg candesartan cilexetil or 50 mg losartan for seven days. On day 1 and day 8, dynamics and kinetics were assessed up to 48 h after dosing. Antagonistic effect was determined from the antagonist-induced rightward shifts of the diastolic blood pressure response curves to exogenously administered angiotensin II measured as the dose ratio (DR). The antagonistic activity in plasma was measured using an ex-vivo/in-vitro radioreceptor assay. Specific high-performance liquid chromatography assays determined plasma concentrations of candesartan, losartan and its active metabolite EXP-3174. The pharmacokinetic properties of candesartan and losartan were comparable and antagonistic activity in plasma almost identical (ratio candesartan: losartan = 0.97 and 1-2 after single and multiple doses, respectively). However, the antagonistic effects of candesartan and losartan in-vivo were quite different. Twenty-four hours after single dosing with candesartan a clinically relevant rightward shift in the angiotensin II dose-response curve (DR= 3.2) occurred that was more pronounced than that following losartan administration (DR=2.1, ratio candesartan: losartan= 1.65). Twenty-four hours after multiple doses of candesartan or losartan, the values of the DR were 4.8 and 2.3, respectively (ratio candesartan: losartan = 1.94). The values of DR for candesartan were significantly higher compared with losartan between 6 and 36h after a single dose and between 3 and 24 h post-dose following multiple dose administration. A counter-clockwise hysteresis was apparent between antagonistic activity in plasma and antagonistic effect. Despite equivalent angiotensin II antagonistic activity in plasma, the pharmacodynamic effect of candesartan cilexetil was greater than that of losartan. Candesartan appeared to have a slower off-rate from the angiotensin AT1-receptor compared with losartan, nevertheless differences in distributional phenomena or the extent of insurmountable antagonistic activity cannot be ruled out.

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…Antagonism of AT1R by various ARBs has also been tested in vivo in humans, mostly healthy volunteers, and, similar to the above animal studies, this was largely done for ANGinduced blood pressure elevations. Following the original study with losartan (Christen et al, 1991), such studies have been performed with candesartan (Delacretaz et al, 1995;Ogihara et al, 1995;Belz et al, 1997Belz et al, , 2000Malerczyk et al, 1998;Fuchs et al, 2000;Gleiter et al, 2004), irbesartan (Belz et al, 1999Maillard et al, 1999;Mazzolai et al, 1999), losartan (Munafo et al, 1992;Belz et al, 1997Belz et al, , 1999Belz et al, , 2000Maillard et al, 1999;Mazzolai et al, 1999;Fuchs et al, 2000;Gleiter et al, 2004), telmisartan Stangier et al, 2001), and valsartan (Müller et al, 1994;Morgan et al, 1997;Belz et al, 1999Belz et al, , 2000Maillard et al, 1999;Mazzolai et al, 1999).…”

“…By using such approaches it was found that candesartan yields a stronger inhibition of ANGinduced blood pressure elevation than losartan for a given level of receptor occupancy, indicating greater affinity and/or slower off-rate from receptor (Belz et al, 1997;Fuchs et al, 2000). Direct comparative studies from these investigators also showed an order of potency of irbesartan .…”

The MUSCAT Study: A Multicenter PROBE Study Comparing the Effects of Angiotensin II Type-1 Receptor Blockers on Self-Monitored Home Blood Pressure in Patients with Morning Hypertension: Study Design and Background Characteristics

“…Other authors observed different durations of action and different efficacies among four ARBs examined herein (21). Further, some studies have shown differences in antihypertensive effect among ARBs using ABPM (22)(23)(24). However, these studies have all been relatively short, with durations of about 1 month or, in the case of our own previous study, no more than 3 months.…”

Candesartan

“…Candesartan cilexetil (8 mg/d) and losartan (50 mg/d) for 7 days appeared to produce different pharmacodynamic effects as assessed by the rightward shift of the angiotensin II dose-response curve. In healthy volunteers the angiotensin II antagonistic effect of candesartan cilexetil was longer-lasting than that of losartan (31).…”