title: The pharmacodynamics and pharmacokinetics of a novel thromboxane receptor blocking drug vapiprost (GR32191) after single intravenous doses in healthy subjects.
abstract: 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)
authors.affiliation: Department of Clinical Pharmacology, Glaxo Group Research, Ware, Herts.
authors.forename: M
authors.initials: M
authors.lastname: Thomas
authors.forename: R J
authors.initials: RJ
authors.lastname: Keery
authors.forename: M K
authors.initials: MK
authors.lastname: Charter
authors.forename: N L
authors.initials: NL
authors.lastname: Scully
authors.forename: J E
authors.initials: JE
authors.lastname: Chilton
authors.forename: P
authors.initials: P
authors.lastname: Lumley
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000328:Adult; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure; D004562:Electrocardiography; D006207:Half-Life; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010366:Peak Expiratory Flow Rate; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011674:Pulse / Q000187:drug effects; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane
chemical_list: D001713:Biphenyl Compounds; D006538:Heptanoic Acids; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C060013:vapiprost