The pharmacokinetics and pharmacologic effects of a potent, selective inhibitor of
thromboxane synthetase,
CV-4151 [(E)-7-phenyl-7-(3-pyridyl)-6-heptenoic
acid] on
prostanoid formation and platelet aggregation were studied in 42 healthy male volunteers. The
drug was well tolerated. After
oral administration of 10 to 100 mg of
CV-4151, peak plasma levels of 1-6 micrograms/mL were reached in a dose-dependent manner within 1 hour. Elimination followed first-order fashion with elimination half-life of about 1 hour. Serum levels of
thromboxane B2 reduced to 4% to 15% of control at 2 hours after
drug ingestion dose-dependently. Serum levels of 6-keto-prostaglandin F1 alpha increased to about four to six times basal levels. Platelet aggregation induced by
collagen and arachidonate was inhibited in most cases. Such pharmacologic effects outlasted serum
drug levels. In repeated administration, stable inhibition of serum
thromboxane B2 production and platelet aggregation in proportion to the enhancement of serum 6-keto-prostaglandin F1 alpha production was observed although no
drug accumulation was found. These results indicate that
CV-4151 may be suitable for clinical trials in
cardiovascular diseases in which imbalance between
thromboxane and
prostacyclin may be involved in the pathogenesis.