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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)
AuthorsA J Nichols, J A Vasko, P F Koster, R E Valocik, G R Rhodes, C Miller-Stein, V Boppana, J M Samanen
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 270 Issue 2 Pg. 614-21 (Aug 1994) ISSN: 0022-3565 [Print] United States
PMID8071853 (Publication Type: Journal Article)
Chemical References
  • Peptides, Cyclic
  • Platelet Aggregation Inhibitors
  • Platelet Membrane Glycoproteins
  • SK&F 106760
  • Fibrin
  • Streptokinase
Topics
  • Animals
  • Blood Platelets (physiology)
  • Coronary Thrombosis (drug therapy)
  • Dogs
  • Fibrin (metabolism)
  • Male
  • Peptides, Cyclic (pharmacology)
  • Platelet Aggregation Inhibitors (pharmacology)
  • Platelet Membrane Glycoproteins (antagonists & inhibitors)
  • Streptokinase (pharmacology)

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