Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects.
BACKGROUND
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.


CONCLUSIONS
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.
Weber
C
C
Clinical and Preclinical Research and Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Schmitt
R
R
Birnboeck
H
H
Hopfgartner
G
G
van Marle
S P
SP
Peeters
P A
PA
Jonkman
J H
JH
Jones
C R
CR
D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D019334:Endothelin-3 / Q000097:blood; D016232:Endothelins / Q000008:administration & dosage / Q000097:blood*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007271:Injections, Intradermal; D007275:Injections, Intravenous; D008297:Male; D011498:Protein Precursors / Q000097:blood; D012016:Reference Values; D012867:Skin / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D016232:Endothelins; D011498:Protein Precursors; D013449:Sulfonamides; C093240:proendothelin 1; D000077300:Bosentan