Dose-Dependent Acute and Sustained Renal Effects of the Endothelin Receptor Antagonist Avosentan in Healthy Subjects

被引:30
作者
Smolander, J. [1 ]
Vogt, B. [1 ]
Maillard, M. [1 ]
Zweiacker, C. [1 ]
Littke, T. [2 ]
Hengelage, T. [2 ]
Burnier, M. [1 ]
机构
[1] CHU Vaudois, Dept Med, Serv Nephrol, CH-1011 Lausanne, Switzerland
[2] Speedel Pharma, Basel, Switzerland
关键词
ANGIOTENSIN-CONVERTING ENZYME; CLINICAL-TRIALS; HEART-FAILURE; INHIBITION; PHARMACOKINETICS; KIDNEY; PHARMACODYNAMICS; LOCALIZATION; PROGRESSION; ATRASENTAN;
D O I
10.1038/clpt.2009.15
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The endothelin receptor antagonist avosentan may cause fluid overload at doses of 25 and 50 mg, but the actual mechanisms of this effect are unclear. We conducted a placebo-controlled study in 23 healthy subjects to assess the renal effects of avosentan and the dose dependency of these effects. Oral avosentan was administered once daily for 8 days at doses of 0.5, 1.5, 5, and 50 mg. The drug induced a dose-dependent median increase in body weight, most pronounced at 50 mg (0.8 kg on day 8). Avosentan did not affect renal hemodynamics or plasma electrolytes. A dose-dependent median reduction in the fractional renal excretion of sodium was found (up to 8.7% at avosentan 50 mg); this reduction was paralleled by a dose-related increase in proximal sodium reabsorption. It is suggested that avosentan dose-dependently induces sodium retention by the kidney, mainly through proximal tubular effects. The potential clinical benefits of avosentan should therefore be investigated at doses of <= 5 mg.
引用
收藏
页码:628 / 634
页数:7
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