INTRODUCTION: Bosentan (Ro 47-0203) is a potent and mixed ETA-and ETB-receptor antagonist. Its activity has been studied in a variety of preclinical disease models. METHODS: Two double-blind placebo-controlled studies were performed to investigate the pharmacokinetics and pharmacodynamics of bosentan after 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 ascending oral dose study, and doses of 10, 50, 250, 500, and 750 mg were given in a single ascending intravenous dose study (six subjects received active drug and two received placebo at each dose level). In an open-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, and skin responses to intradermally injected endothelin-1 (ET-1) were recorded, 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. RESULTS: Systemic plasma clearance and volume of distribution decreased with increasing dose to limiting values of around 6 L/hr and 0.2 L/kg, respectively. The absolute bioavailability was 50% and appeared to decrease with doses above 600 mg. Plasma ET-1 increased maximally twofold (oral) and threefold (intravenous), and this increase was directly related to bosentan plasma concentrations according to an Emax model. Bosentan reversed the vasoconstrictor effect of ET-1 measured in the skin microcirculation. There was a tendency toward decreased blood pressure (approximately 5 mm Hg) and increased pulse rate (approximately 5 beats/min), neither was clearly dose dependent. Oral bosentan was well tolerated. Vomiting and local intolerability was observed at the higher intravenous doses. CONCLUSION: Bosentan is an orally bioavailable, well-tolerated, and active ET-1 antagonist with a low clearance and a moderate volume of distribution. Its intravenous use is limited because of local intolerability.