Clopidogrel and prasugrel belong to a thienopyridine class of oral anti-platelet drugs that, after having been metabolized in the liver, can inhibit platelet function by irreversibly antagonizing the P2Y12 receptor. Furthermore, thienopyridines influence numerous inflammatory conditions but their effects on neutrophils have not been evaluated, despite the important role of these cells in inflammation. Therefore, we investigated the effect of prasugrel metabolites on neutrophils to further clarify the role of thienopyridines in inflammation. Interestingly, a prasugrel metabolite mixture, produced in vitro using rat liver microsomes, significantly inhibited fMLP- and PAF-induced neutrophil activation. More specifically, prasugrel metabolites inhibited neutrophil transmigration, CD16 surface expression, and neutrophil-platelet aggregation. Moreover, prasugrel metabolite pre-treatment also significantly decreased fMLP- or PAF-induced ERK phosphorylation as well as calcium mobilization. To determine the target of prasugrel in neutrophils, the role of both P2Y12 and P2Y13 receptors was studied using specific reversible antagonists, AR-C69931MX and MRS2211, respectively. Neither antagonist had any direct effect on the agonist-induced neutrophil functional responses. Our findings indicate that prasugrel metabolites may directly target neutrophil and inhibit their activation, suggesting a possible explanation for their anti-inflammatory effects previously observed. However, these metabolites do not act through either the P2Y12 or P2Y13 receptor in neutrophils.
- Received April 30, 2012.
- Revision received October 22, 2012.
- Accepted October 23, 2012.
- The American Society for Pharmacology and Experimental Therapeutics