Thromb Haemost 2007; 98(01): 192-200
DOI: 10.1160/TH07-01-0010
Platelets and Blood Cells
Schattauer GmbH

The active metabolite of prasugrel inhibits ADP-stimulated thrombo-inflammatory markers of platelet activation: Influence of other blood cells, calcium, and aspirin

Andrew L. Frelinger III
1   Center for Platelet Function Studies
3   Pediatrics and
,
Joseph A. Jakubowski
5   Lilly Research Laboratories, Indianapolis, Indiana, USA
,
You FuLi
1   Center for Platelet Function Studies
3   Pediatrics and
,
Marc R. Barnard
1   Center for Platelet Function Studies
3   Pediatrics and
,
Marsha L. Fox
1   Center for Platelet Function Studies
3   Pediatrics and
,
Matthew D. Linden
1   Center for Platelet Function Studies
3   Pediatrics and
,
Atsuhiro Sugidachi
6   Daiichi Sankyo Company Ltd., Tokyo, Japan
,
Kenneth J. Winters
5   Lilly Research Laboratories, Indianapolis, Indiana, USA
,
Mark I. Furman
1   Center for Platelet Function Studies
2   Division of Cardiovascular Medicine, and Departments of
4   Medicine, University of Massachusetts Medical School, Worcester, Massachussetts, USA
,
Alan D. Michelson
1   Center for Platelet Function Studies
3   Pediatrics and
4   Medicine, University of Massachusetts Medical School, Worcester, Massachussetts, USA
› Institutsangaben

Financial support: This work was supported by a grant to Drs. Frelinger and Michelson from Eli Lilly & Co. and Daiichi Sankyo Co., Ltd. Dr. Furman receives research support from Eli Lilly & Co. and is a member of the Speakers’ Bureau of Sanofi-Aventis. Drs. Jakubowski and Winters are employees of Eli Lilly & Co. Dr. Sugidachi is an employee of Daiichi Sankyo Co., Ltd.
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Publikationsverlauf

Received 05. Januar 2007

Accepted after resubmission 28. März 2007

Publikationsdatum:
29. November 2017 (online)

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Summary

The novel thienopyridine prodrug prasugrel, a platelet P2Y12 ADP receptor antagonist, requires in vivo metabolism for activity. Although pharmacological data have been collected on the effects of prasugrel on platelet aggregation,there are few data on the direct effects of the prasugrel’s active metabolite, R-138727, on other aspects of platelet function. Here we examined the effects of R-138727 on thrombo-inflammatory markers of platelet activation, and the possible modulatory effects of other blood cells, calcium, and aspirin. Blood (PPACK or citrate anticoagulated) from healthy donors pre- and post-aspirin was incubated with R-138727 and the response to ADP assessed in whole blood or platelet-rich plasma (PRP) by aggregometry and flow cytometric analysis of leukocyte-platelet aggregates,platelet surface P-selectin, and GPIIb-IIIa activation. Low-micromolar concentrations of R-138727 resulted in a rapid and consistent in-hibition of these ADP-stimulated thrombo-inflammatory markers.These rapid kinetics required physiological calcium levels, but were largely unaffected by aspirin. Lower IC50 values in whole blood relative to PRP suggested that other blood cells affect ADP-induced platelet activation and hence the net inhibition by R-138727. R-138727 did not inhibit P2Y12-mediated ADP-induced shape change, even at concentrations that completely inhibited platelet aggregation, confirming the specificity of R-138727 for P2Y12. In conclusion, R-138727, the active metabolite of prasugrel, results in rapid, potent, consistent, and selective inhibition of P2Y12-mediated up-regulation of thromboinflammatory markers of platelet activation.This inhibition is enhanced in the presence other blood cells and calcium,but not aspirin.