title: Dose-dependent acute and sustained renal effects of the endothelin receptor antagonist avosentan in healthy subjects.
abstract: 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.
authors.affiliation: Service de Néphrologie, Département de Médecine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Smolander
authors.forename: B
authors.initials: B
authors.lastname: Vogt
authors.forename: M
authors.initials: M
authors.lastname: Maillard
authors.forename: C
authors.initials: C
authors.lastname: Zweiacker
authors.forename: T
authors.initials: T
authors.lastname: Littke
authors.forename: T
authors.initials: T
authors.lastname: Hengelage
authors.forename: M
authors.initials: M
authors.lastname: Burnier
mesh_terms: 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
chemical_list: D004573:Electrolytes; D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; D012964:Sodium; C484919:Avosentan