Pharmacokinetic-pharmacodynamic interactions of candesartan cilexetil and losartan

被引:18
作者
Azizi, M
Chatellier, G
Guyene, TT
Ménard, J
机构
[1] Hop Broussais, Clin Invest Ctr, INSERM, F-75674 Paris 14, France
[2] Assistance Publ Hop Paris, Paris, France
关键词
blood pressure; renin; AT(1) receptor blockers; pharmacokinetics; pharmacodynamics;
D O I
10.1097/00004872-199917040-00015
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
Background The variability of the blood pressure response to blockade of the angiotensin II type 1 receptor is influenced by renin status and pharmacokinetics and pharmacokinetic-pharmacodynamic interactions. Objective To compare the pharmacokinetic-pharmacodynamic interactions of two doses of an ester prodrug of a noncompetitive angiotensin II type 1 receptor antagonist, candesartan cilexetil, at 8 and 16 mg, with those of the reference angiotensin II type 1 receptor blocker, losartan, at the standard dose (50 mg), in a human model that controls renin status. Design and methods In a double-blind placebo-controlled crossover study, we compared the effects on renin and mean blood pressure over 24 h of single oral doses of candesartan cilexetil at 8 and 16 mg and losartan at 50 mg in 16 sodium-depleted normotensive subjects. Results The area under the curve (0-24 h) for plasma active renin did not differ significantly between 8 mg candesartan cilexetil and 50 mg losartan, but was significantly higher for 16 than for 8 mg candesartan cilexetil or for 50 mg losartan. The area under the curve (0-24 h) for the fall in mean blood pressure with 16 mg candesartan cilexetil (-197 +/- 96 mmHg/h) was significantly greater than that for placebo (-112 +/- 81 mmHg/h; P < 0.05) but the difference was not statistically significant compared with either 8 mg candesartan cilexetil (-158 +/- 95 mmHg/h) or 50 mg losartan (-144 +/- 66 mmHg/h). The area under the curve (0-24 h) for the fall in mean blood pressure did not significantly differ between 8 mg candesartan cilexetil, 50 mg losartan and placebo. The area under the curve (0-24 h) for plasma active renin was significantly correlated to that for plasma levels of the active metabolite of losartan, EXP 3174 (r = 0.65, n = 16, P < 0.01). No such correlation was detected for each single dose of candesartan cilexetil but a dose-response relationship was present when both doses were combined. Conclusions The pharmacodynamic effects of a single oral dose of 16 mg candesartan cilexetil are greater than those of 50 mg losartan and 8 mg candesartan cilexetil. The variability in the pharmacokinetic-pharmacodynamic interaction is less pronounced for candesartan than for EXP 3174, which could result in reduced variability of the blood pressure effects in patients. J Hypertens 1999, 17:561-568 (C) Lippincott Williams & Wilkins.
引用
收藏
页码:561 / 568
页数:8
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