title: Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A.
abstract: 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.
authors.affiliation: Division of Nephrology, University Hospital Basel, Basel, Switzerland. isabelle.binet@nds.ox.ac.uk
authors.forename: I
authors.initials: I
authors.lastname: Binet
authors.forename: A
authors.initials: A
authors.lastname: Wallnöfer
authors.forename: C
authors.initials: C
authors.lastname: Weber
authors.forename: R
authors.initials: R
authors.lastname: Jones
authors.forename: G
authors.initials: G
authors.lastname: Thiel
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D016572:Cyclosporine / Q000008:administration & dosage*; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010919:Placebos; D012016:Reference Values; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D065128:Endothelin Receptor Antagonists; D010919:Placebos; D013449:Sulfonamides; D016572:Cyclosporine; D000077300:Bosentan