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Titolo:
Identification and biological activity of the active metabolite of clopidogrel
Autore:
Savi, P; Pereillo, JM; Uzabiaga, MF; Combalbert, J; Picard, C; Maffrand, JP; Pascal, M; Herbert, JM;
Indirizzi:
Sanofi Synthelabo, Cardiovasc Thrombosis Res Dept, F-31036 Toulouse, France Sanofi Synthelabo Toulouse France F-31036 Dept, F-31036 Toulouse, France Sanofi Synthelabo, Labege, France Sanofi Synthelabo Labege FranceSanofi Synthelabo, Labege, France
Titolo Testata:
THROMBOSIS AND HAEMOSTASIS
fascicolo: 5, volume: 84, anno: 2000,
pagine: 891 - 896
SICI:
0340-6245(200011)84:5<891:IABAOT>2.0.ZU;2-#
Fonte:
ISI
Lingua:
ENG
Soggetto:
PLATELET ADENYLATE-CYCLASE; RAT PLATELETS; ANTIAGGREGATING ACTIVITY; BLOOD-PLATELETS; IN-VITRO; ADP; RECEPTOR; INHIBITION; BINDING; TICLOPIDINE;
Keywords:
clopidogrel; ADP; aggregation; platelets; metabolite;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
26
Recensione:
Indirizzi per estratti:
Indirizzo: Herbert, JM Sanofi Synthelabo, Cardiovasc Thrombosis Res Dept, 195 Route Espagne, F-31036 Toulouse, France Sanofi Synthelabo 195 Route Espagne Toulouse France F-31036 e
Citazione:
P. Savi et al., "Identification and biological activity of the active metabolite of clopidogrel", THROMB HAEM, 84(5), 2000, pp. 891-896

Abstract

Like ticlopidine, the ADP receptor antagonist clopidogrel is inactive in vitro and must be administered i.v. or orally to exhibit antiaggregatory andantithrombotic activities. We have previously shown that hepatic metabolism is necessary for activity. This study demonstrates that an active metabolite can be generated from human liver microsomes incubated with clopidogrel. Using several analytical methodologies (LC/MS, NMR, chiral supercritical fluid chromatography), we heave identified its structure. lit vitro, this highly unstable compound, different from that formed from ticlopidine, exhibited all the biological activities of clopidogrel observed ex vivo: Irreversible inhibition of the binding of P-33-2MeS-ADP to washed human platelets (IC50 = 0.53 muM), selective inhibition of ADP-induced platelet aggregation(IC = 1.8 muM) and ADP-induced adenylyl cyclase down-regulation. The irreversible modification of the ADP-receptor site which is responsible for the biological activity could be explained by the formation of a disulfide bridge between the reactive thiol group of the active metabolite and a cysteineresidue of the platelet ADP receptor.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 21/09/20 alle ore 17:00:40