Article date: June 2004
By: Kenji Yoneda, Ryou Iwamura, Hiroko Kishi, Yoichi Mizukami, Kimiko Mogami, Sei Kobayashi in Volume 142, Issue 3, pages 551-557
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.
An active moiety (UR‐4501) was isolated by high‐performance liquid chromatography after large‐scale preparation of metabolites.
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.
UR‐4501 produced a concentration‐dependent inhibition (3–100 μM) of ADP (10 μM)‐induced human platelet aggregation, whereas 2‐oxo‐ticlopidine (3–100 μM) did not elicit inhibitory responses.
UR‐4501 (10–100 μM) strongly inhibited ADP‐ and collagen‐induced aggregation and slightly inhibited thrombin‐induced aggregation.
The inhibition of rat washed platelet aggregation by UR‐4501 (100 μM) persisted, even after the platelets had been washed twice.
These results suggest that UR‐4501 is the molecule responsible for the in vivo activities of ticlopidine.
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.
An active moiety (UR‐4501) was isolated by high‐performance liquid chromatography after large‐scale preparation of metabolites.
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.
UR‐4501 produced a concentration‐dependent inhibition (3–100 μM) of ADP (10 μM)‐induced human platelet aggregation, whereas 2‐oxo‐ticlopidine (3–100 μM) did not elicit inhibitory responses.
UR‐4501 (10–100 μM) strongly inhibited ADP‐ and collagen‐induced aggregation and slightly inhibited thrombin‐induced aggregation.
The inhibition of rat washed platelet aggregation by UR‐4501 (100 μM) persisted, even after the platelets had been washed twice.
These results suggest that UR‐4501 is the molecule responsible for the in vivo activities of ticlopidine.
British Journal of Pharmacology (2004) 142, 551–557. doi:10.1038/sj.bjp.0705808
DOI: 10.1038/sj.bjp.0705808
View this article