Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A

Kidney Int. 2000 Jan;57(1):224-31. doi: 10.1046/j.1523-1755.2000.00838.x.


Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A.

Background: Endothelins may play an important role in cyclosporine A (CsA)-induced renal vasoconstriction. Therefore, the effects of a mixed endothelin A and B receptor antagonist, bosentan (BO), on CsA were studied.

Methods: BO was given either alone or combined with CsA to healthy subjects in a double-blind, placebo-controlled, cross-over study. Standardized renal hemodynamics took place after a single dose of BO or placebo and after seven days of regular intake of CsA + BO or CsA + placebo. CsA was administered as a dose-adjusted regimen to achieve predetermined target trough levels. A pharmacokinetic study of CsA and BO was performed.

Results: A single dose of BO did not affect renal hemodynamics. After seven days of coadministration with CsA, BO significantly attenuated both the overall CsA-induced fall of renal plasma flow (RPF; placebo, 594 +/- 85; CsA + placebo, 490 +/- 93; CsA + BO, 570 +/- 106* mL/min, *P < 0.01) and the maximal RPF fall (P < 0.01) observed five hours after CsA intake. The CsA-induced rise of blood pressure and the decrease of glomerular filtration rate (GFR) were not influenced by comedication with BO. After seven days of CsA + BO, the area under the curve (AUC) of BO was nearly doubled compared with the AUC after a single dose of BO (P < 0.05). To reach the CsA target trough levels after seven days, the average CsA dose was increased by 35% when given with BO, as compared with placebo (P = 0.01). CsA exposure (trough levels, AUC) was not statistically different after CsA + placebo and after CsA + BO.

Conclusions: Assuming CsA nephrotoxicity is mainly due to vasoconstriction, BO has the potential to attenuate the CsA renal toxicity by markedly blunting the renal hypoperfusion effect of CsA. A complex drug interaction between BO and CsA was observed.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Pressure / drug effects
  • Bosentan
  • Cyclosporine / administration & dosage*
  • Double-Blind Method
  • Endothelin Receptor Antagonists
  • Humans
  • Kidney / drug effects*
  • Kidney / physiology
  • Male
  • Placebos
  • Reference Values
  • Sulfonamides / administration & dosage
  • Sulfonamides / adverse effects
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology*


  • Endothelin Receptor Antagonists
  • Placebos
  • Sulfonamides
  • Cyclosporine
  • Bosentan