Identification of the active metabolite of ticlopidine from rat in vitro metabolites

Br J Pharmacol. 2004 Jun;142(3):551-7. doi: 10.1038/sj.bjp.0705808. Epub 2004 May 17.

Abstract

1 Ticlopidine is a well-known anti-platelet agent, but is not active by itself in vitro. We identified a metabolite with anti-platelet activity, which was generated after incubation of 2-oxo-ticlopidine with phenobarbital-induced rat liver homogenate in vitro. 2 An active moiety (UR-4501) was isolated by high-performance liquid chromatography after large-scale preparation of metabolites. 3 The chemical structure of UR-4501 was determined by a combination of liquid chromatography mass/mass spectrometry (LC/MS/MS) and nuclear magnetic resonance (NMR) analysis. 4 UR-4501 produced a concentration-dependent inhibition (3-100 microm) of ADP (10 microm)-induced human platelet aggregation, whereas 2-oxo-ticlopidine (3-100 microm) did not elicit inhibitory responses. 5 UR-4501 (10-100 microm) strongly inhibited ADP- and collagen-induced aggregation and slightly inhibited thrombin-induced aggregation. 6 The inhibition of rat washed platelet aggregation by UR-4501 (100 microm) persisted, even after the platelets had been washed twice. 7 These results suggest that UR-4501 is the molecule responsible for the in vivo activities of ticlopidine.

MeSH terms

  • Animals
  • Chromatography, High Pressure Liquid
  • Humans
  • In Vitro Techniques
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Nipecotic Acids / isolation & purification
  • Nipecotic Acids / pharmacology*
  • Phenobarbital / pharmacology
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation Inhibitors / metabolism*
  • Platelet Aggregation Inhibitors / pharmacology
  • Rats
  • Rats, Wistar
  • Sulfhydryl Compounds / isolation & purification
  • Sulfhydryl Compounds / pharmacology*
  • Ticlopidine / metabolism*
  • Ticlopidine / pharmacology

Substances

  • Nipecotic Acids
  • Platelet Aggregation Inhibitors
  • Sulfhydryl Compounds
  • UR 4501
  • Ticlopidine
  • Phenobarbital