PHARMACOKINETICS AND PHARMACODYNAMICS OF THE ENDOTHELIN-RECEPTOR ANTAGONIST BOSENTAN IN HEALTHY-HUMAN SUBJECTS

Methods: Two double-blind placebo-controlled studies were performed to investigate the pharmacokinetics and pharmacodynamics of bosentan aft er single oral and intravenous doses in healthy volunteers; doses of 3 , 10, 30, 100, 300, 600, 1200, and 2400 mg were given in a single asce nding oral dose study, and doses of 10, 50, 250, 500, and 750 mg were given in a single ascending intravenous dose study (six subjects recei ved active drug and two received placebo at each dose level). In an op en-label crossover added to the second study, six subjects received a single oral dose of 600 mg and a single intravenous dose of 250 mg in randomized order. At regular intervals, blood pressure, pulse rate, an d skin responses to intradermally injected endothelin-1 (ET-1) were re corded, and plasma levels of ET-1, proendothelin-1 (big ET-1), and ET- 3, and drug and urinary levels of ET-1 and drug were determined. Resul ts: Systemic plasma clearance and volume of distribution decreased wit h increasing dose to limiting values of around 6 L/hr and 0.2 L/kg, re spectively. The absolute bioavailability was 50% and appeared to decre ase with doses above 600 mg. Plasma ET-1 increased maximally twofold ( oral) and threefold (intravenous), and this increase was directly rela ted to bosentan plasma concentrations according to an E(max) model. Bo sentan reversed the vasoconstrictor effect of ET-1 measured in the ski n microcirculation. There was a tendency toward decreased blood pressu re (approximately 5 mm Hg) and increased pulse rate (approximately 5 b eats/min), neither was clearly dose dependent. Oral bosentan was well tolerated, Vomiting and local intolerability was observed at the highe r intravenous doses. Conclusion: Bosentan is an orally bioavailable, w ell-tolerated, and active ET-1 antagonist with a low clearance and a m oderate volume of distribution. Its intravenous use is limited because of local intolerability.