The pharmacodynamics and pharmacokinetics of a novel thromboxane receptor blocking drug vapiprost (GR32191) after single intravenous doses in healthy subjects.

1 The effect of single, serially increasing, intravenous doses of a specific thromboxane receptor blocking drug, vapiprost, upon platelet aggregation induced ex vivo by the thromboxane A2 mimetic, U‐46619, was examined in 12 healthy males. 2 Subjects received either 1 (n = 1 subject), 2 (n = 6), 3 (n = 2), or 4 (n = 3) administrations of vapiprost within the dose range 0.125 to 16 mg and, in random order, placebo on separate study days at intervals of at least 48 h. 3 All doses of vapiprost produced an immediate antagonism of U‐46619‐induced platelet aggregation in whole blood. Both the magnitude and duration of the rightward displacement of the concentration‐effect curves increased with dose. Although lower doses produced parallel displacements of these curves, with the higher doses the maximum response to U‐46619 was reduced such that 50% platelet aggregation was not achieved. After the 16 mg dose of vapiprost, virtually complete suppression of platelet aggregation (up to a concentration of 30 microM) was seen. This degree of inhibition was maintained for 2 h after dosing, following which there was a gradual return to pre‐dose U‐46619 sensitivity over the next 12 to 24 h. U‐46619‐induced platelet aggregation was unaffected by placebo. 4 Across the dose range, vapiprost was rapidly cleared from plasma, with an elimination half‐life of 69‐84 min and a plasma clearance of 514‐721 ml min‐1.(ABSTRACT TRUNCATED AT 250 WORDS)

DOI: 10.1111/j.1365-2125.1991.tb03879.x

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