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Pharmacokinetics and pharmacodynamics of the endothelin‐receptor antagonist bosentan in healthy human subjects
Author(s) -
Weber Cornelia,
Schmitt Rita,
Birnboeck Herbert,
Hopfgartner Gerard,
Marle Sjoerd P.,
Peeters Pierre A.M.,
Jonkman Jan H.G.,
Jones CharlesRichard
Publication year - 1996
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(96)90127-7
Subject(s) - bosentan , pharmacokinetics , endothelin receptor antagonist , pharmacodynamics , medicine , crossover study , pharmacology , endothelin receptor , placebo , bioavailability , volume of distribution , receptor , alternative medicine , pathology
Bosentan (Ro 47‐0203) is a potent and mixed ET A ‐ and ET B ‐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 E max 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. Clinical Pharmacology & Therapeutics (1996) 60 , 124–137; doi: