Dose-dependent acute and sustained renal effects of the endothelin receptor antagonist avosentan in healthy subjects.
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 <or= 5 mg.
Smolander
J
J
Service de Néphrologie, Département de Médecine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Vogt
B
B
Maillard
M
M
Zweiacker
C
C
Littke
T
T
Hengelage
T
T
Burnier
M
M
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004573:Electrolytes / Q000097:blood / Q000652:urine; D065128:Endothelin Receptor Antagonists; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D008297:Male; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D012039:Regional Blood Flow / Q000187:drug effects; D012964:Sodium / Q000378:metabolism; D055815:Young Adult
D004573:Electrolytes; D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; D012964:Sodium; C484919:Avosentan