Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A.
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.
Binet
I
I
Division of Nephrology, University Hospital Basel, Basel, Switzerland. isabelle.binet@nds.ox.ac.uk
Wallnöfer
A
A
Weber
C
C
Jones
R
R
Thiel
G
G
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*
D065128:Endothelin Receptor Antagonists; D010919:Placebos; D013449:Sulfonamides; D016572:Cyclosporine; D000077300:Bosentan