Multiple‐Dose Pharmacokinetics, Safety, and Tolerability of Bosentan, an Endothelin Receptor Antagonist, in Healthy Male Volunteers

Abstract

The multiple-dose pharmacokinetics, safety, and tolerability of oral bosentan, a selective endothelin receptor antagonist, were investigated in healthy male volunteers. In study A, an ascending-dose, double-blind, placebo-controlled trial, doses of 100, 200, 500, and 1000 mg bosentan or placebo were given once daily for 8 days as tablets (100 and 500 mg dose strength). In study B, a double-blind, placebo-controlled trial, 500 mg tablets of bosentan or placebo tablets were given once daily for 8 days with two additional single intravenous dose administrations of 250 mg bosentan 48 hours before the first and 24 hours after the last oral dose. The drug was very well tolerated. No effects on pulse rate, ECGs, or clinical laboratory tests were observed. Marginal effects on blood pressure were seen in subjects only when standing. The oral bioavailability of bosentan was 43% to 48%, with a small interindividual variability of 20%. Doses above 500 mg did not lead to significant further increases in plasma levels of bosentan. From the first to the last day of the oral treatment phase, plasma concentrations of bosentan decreased by 30% to 40% due to a 2-fold increase in plasma clearance. Absorption and plasma protein binding did not change. The 24-hour urinary excretion of 6 beta-hydroxycortisol was increased in parallel by approximately 1.7-fold, indicating induction of cytochrome P450 3A isozymes. The two metabolites of bosentan reached plasma concentrations well below those of bosentan and will most likely not contribute to the pharmacological activity.

Endothelin Axis Is Upregulated in Human and Rat Right Ventricular Hypertrophy

“…29,30 Both hypertrophied and normal RV hearts showed an increase in developed pressure from baseline when treated with the β-agonist isoproterenol or ET-1 ( Figure 4A and 4B). Two different ERAs (the ET R -A antagonist BQ-123 and bosentan, a nonselective ERA used in PAH) 37,38 caused a significant and reversible decrease in RV developed pressure in hypertrophied, but not normal RVs ( Figure 4A and 4B, Online Figure V). The negative RV inotropic effect of bosentan was dose-dependent.…”

“…The dose-dependent effects of bosentan on RV contractility/ lucitropy at doses within the range of bosentan serum levels in treated patients 37,38 suggest that they are clinically relevant. Because BQ-123 had the same effects, this is likely an ERA class effect.…”

Differential Inhibition of Rat and Human Na+-Dependent Taurocholate Cotransporting Polypeptide (NTCP/SLC10A1)by Bosentan: A Mechanism for Species Differences in Hepatotoxicity

“…At the therapeutically relevant unbound plasma concentrations of bosentan in patients (C max 2 M, 98% protein-bound) (Weber et al, 1999), no significant inhibition in bile acid uptake by human NTCP would be expected. Thus, differential inhibition of bile acid uptake and efflux could account for differences between rats and humans in susceptibility to bosentan-induced hepatotoxicity.…”

in silico and Physico-Chemical Assessment of Effectiveness of Hydroxy/Amino Acids as Auxiliary Substances to Improve the Complexation Efficiency of ββ ββ β-Cyclodextrin Towards Bosentan

“…1) is a white crystalline powder acting as non-peptide antagonist of human endothelial-I receptor [1]. It is mainly recommended in the treatment of pulmonary arterial hypertension [2].…”