title: The in vivo pharmacological profile of the novel glycoprotein IIb/IIIa antagonist, SK&F 106760.
abstract: The in vivo pharmacological profile of SK&F 106760 [N alpha-acetyl-cyclo(S,S)-cysteinyl-N alpha-methylarginyl-glycyl-aspartyl-penicillamine-amide], a novel, potent glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist has been investigated. In conscious dogs, SK&F 106760 (0.3-3 mg/kg i.v.) produced a dose-related inhibition of ex vivo whole blood platelet aggregation induced by collagen (5 micrograms/ml) with complete inhibition being produced for 5, 90 and 165 min after administration of 0.3, 1 and 3 mg/kg i.v., respectively. Plasma levels of SK&F 106760 were measured by high-performance liquid chromatography after i.v. bolus administration of 1 mg/kg. An initial alpha-disposition phase with a T1/2 of 11 +/- 6 min was followed by a longer terminal beta-elimination phase with a T1/2 of 66 +/- 12 min, which accounted for 79 +/- 9% of the total area under the plasma concentration-time curve. The apparent steady-state volume of distribution was 259 +/- 26 ml/kg and the plasma clearance was 3.4 +/- 0.8 ml/min/kg. The plasma concentration of SK&F 106760 at which collagen-induced ex vivo whole blood aggregation was inhibited by 50% was estimated to be 593 +/- 52 nM. After intraduodenal and intrajejunal administration of 3 mg/kg, SK&F 106760 had a bioavailability of 3 to 6% and produced a peak inhibition of ex vivo platelet aggregation of 40 to 50%. In anesthetized dogs, SK&F 106760 (0.3-3.0 mg/kg i.v.) produced a complete inhibition of platelet-dependent coronary artery thrombosis, with a dose-related duration of action.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
authors.forename: A J
authors.initials: AJ
authors.lastname: Nichols
authors.forename: J A
authors.initials: JA
authors.lastname: Vasko
authors.forename: P F
authors.initials: PF
authors.lastname: Koster
authors.forename: R E
authors.initials: RE
authors.lastname: Valocik
authors.forename: G R
authors.initials: GR
authors.lastname: Rhodes
authors.forename: C
authors.initials: C
authors.lastname: Miller-Stein
authors.forename: V
authors.initials: V
authors.lastname: Boppana
authors.forename: J M
authors.initials: JM
authors.lastname: Samanen
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D003328:Coronary Thrombosis / Q000188:drug therapy; D004285:Dogs; D005337:Fibrin / Q000378:metabolism; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D013300:Streptokinase / Q000494:pharmacology
chemical_list: D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; C071275:SK&F 106760; D005337:Fibrin; D013300:Streptokinase