The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel's active metabolite.
METHODS
Prasugrel is a novel orally active thienopyridine prodrug with potent and long-lasting antiplatelet effects. Platelet inhibition reflects inhibition of P2Y(12) receptors by its active metabolite (AM). Previous studies have shown that the antiplatelet potency of prasugrel is at least 10 times higher than that of clopidogrel in rats and humans, but the mechanism of its higher potency has not yet been fully elucidated.


RESULTS
Oral administration of prasugrel to rats resulted in dose-related and time-related inhibition of ex vivo platelet aggregation, and its effect was about 10 times more potent than that of clopidogrel. The plasma concentration of prasugrel AM was higher than that of clopidogrel AM despite tenfold higher doses of clopidogrel, indicating more efficient in vivo production of prasugrel AM than of clopidogrel AM. In rat platelets, prasugrel AM inhibited in vitro platelet aggregation induced by adenosine 5'-diphosphate (ADP) (10 microm) with an IC(50) value of 1.8 microm. Clopidogrel AM similarly inhibited platelet aggregation with an IC(50) value of 2.4 microm. Similar results were also observed for ADP-induced (10 microm) decreases in prostaglandin E(1)-stimulated rat platelet cAMP levels. These results indicate that both AMs have similar in vitro antiplatelet activities.


CONCLUSIONS
The greater in vivo antiplatelet potency of prasugrel as compared to clopidogrel reflects more efficient in vivo generation of its AM, which demonstrates similar in vitro activity to clopidogrel AM.
Sugidachi
A
A
Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan.
Ogawa
T
T
Kurihara
A
A
Hagihara
K
K
Jakubowski
J A
JA
Hashimoto
M
M
Niitsu
Y
Y
Asai
F
F
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism*; D000077144:Clopidogrel; D000242:Cyclic AMP / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology*; D000068799:Prasugrel Hydrochloride; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology
D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D013876:Thiophenes; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D000242:Cyclic AMP; D000527:Alprostadil; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine