Identification of the active metabolite of ticlopidine from rat in vitro metabolites.
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.
Yoneda
Kenji
K
Department of Molecular Physiology, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
Iwamura
Ryou
R
Kishi
Hiroko
H
Mizukami
Yoichi
Y
Mogami
Kimiko
K
Kobayashi
Sei
S
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009557:Nipecotic Acids / Q000302:isolation & purification / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000302:isolation & purification / Q000494:pharmacology*; D013988:Ticlopidine / Q000378:metabolism* / Q000494:pharmacology
D009557:Nipecotic Acids; D010975:Platelet Aggregation Inhibitors; D013438:Sulfhydryl Compounds; C495451:UR 4501; D013988:Ticlopidine; D010634:Phenobarbital