The angiotensin II antagonistic effects of candesartan and losartan were co
mpared in-vivo after single and repeated doses. Effects were related to ant
agonistic 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 l
osartan for seven days. On day 1 and day 8, dynamics and kinetics were asse
ssed up to 48 h after dosing. Antagonistic effect was determined from the a
ntagonist-induced rightward shifts of the diastolic blood pressure response
curves to exogenously administered angiotensin II measured as the dose rat
io (DR). The antagonistic activity in plasma was measured using an ex-vivo/
in-vitro radioreceptor assay. Specific high-performance liquid chromatograp
hy 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: lo
sartan = 0.97 and 1.2 after single and multiple doses, respectively). Howev
er, the antagonistic effects of candesartan and losartan in-vivo were quite
different. Twenty-four hours after single dosing with candesartan a clinic
ally relevant rightward shift in the angiotensin II dose-response curve (DR
=3.2) occurred that was more pronounced than that following losartan admini
stration (DR=2.1, ratio candesartan:losartan= 1.65). Twenty-four hours afte
r 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 D
R for candesartan were significantly higher compared with losartan between
6 and 36 h after a single dose and between 3 and 24 h post-dose following m
ultiple dose administration. A counter-clockwise hysteresis was apparent be
tween antagonistic activity in plasma and antagonistic effect.
Despite equivalent angiotensin II antagonistic activity in plasma, the phar
macodynamic effect of candesartan cilexetil was greater than that of losart
an. Candesartan appeared to have a slower off-rate from the angiotensin AT(
1)-receptor compared with losartan, nevertheless differences in distributio
nal phenomena or the extent of insurmountable antagonistic activity cannot
be ruled out.