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 endotheli n 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, crossover study. Standardized renal hemodynamics took place after a single dose of BO or placebo and after sev en days of regular intake of CsA + BO or CsA + placebo. CsA was administere d 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 ov erall 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 ma ximal RPF fall (P < 0.01) observed five hours after CsA intake. The CsA-ind uced 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 trou gh 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 le vels, AUG) was not statistically different after CsA + placebo and after Cs A + BO. Conclusions. Assuming CsA nephrotoxicity is mainly due to vasoconstriction, BO has the potential to attenuate the CsA renal toxicity by markedly blunt ing the renal hypoperfusion effect of CsA. A complex drug interaction betwe en BO and CsA was observed.