Comparative pharmacodynamics and pharmacokinetics of candesartan and losartan in man.
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.
Fuchs
B
B
Center for Cardiovascular Pharmacology, ZeKaPha GmbH, Mainz/Wiesbaden, Pharmacological Institute, Johann-Wolfgang-Goethe-University, Frankfurt Germany.
Breithaupt-Grögler
K
K
Belz
G G
GG
Roll
S
S
Malerczyk
C
C
Herrmann
V
V
Spahn-Langguth
H
H
Mutschler
E
E
D000328:Adult; D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D001713:Biphenyl Compounds; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D019808:Losartan / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D011869:Radioligand Assay; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles / Q000493:pharmacokinetics* / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D019808:Losartan; C081643:candesartan