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Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A
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Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A
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Journal Article
Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A
2000
Overview
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.
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.
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 ß 0.01) and the maximal RPF fall (P ß 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 ß 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.
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.
Publisher
Elsevier Inc,Nature Publishing,Elsevier Limited
Subject
/ Biological and medical sciences
/ Blood Pressure - drug effects
/ Cyclosporine - administration & dosage
/ Endothelin Receptor Antagonists
/ Humans
/ Male
/ Pharmacology. Drug treatments
/ Placebos
/ Sulfonamides - administration & dosage
/ Sulfonamides - adverse effects
