title: Prasugrel metabolites inhibit neutrophil functions.
abstract: Clopidogrel and prasugrel belong to a thienopyridine class of oral antiplatelet drugs that, after having been metabolized in the liver, can inhibit platelet function by irreversibly antagonizing the P2Y(12) 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 N-formyl-methionyl-leucyl-phenylalanine (fMLP)- and platelet-activating factor (PAF)-induced neutrophil activation. More specifically, prasugrel metabolites inhibited neutrophil transmigration, CD16 surface expression, and neutrophil-platelet aggregation. Moreover, prasugrel metabolite pretreatment also significantly decreased fMLP- or PAF-induced extracellular-signal-regulated kinase phosphorylation as well as calcium mobilization. To determine the target of prasugrel in neutrophils, the role of both P2Y(12) and P2Y(13) 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 neutrophils and inhibit their activation, suggesting a possible explanation for their anti-inflammatory effects previously observed. However, these metabolites do not act through either the P2Y(12) or P2Y(13) receptor in neutrophils.
authors.affiliation: Sol Sherry Thrombosis Research Center, Temple University, MRB, 3420 N. Broad Street, Philadelphia, PA 19140, USA. eliliverani@temple.edu
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Liverani
authors.forename: Mario C
authors.initials: MC
authors.lastname: Rico
authors.forename: Analia E
authors.initials: AE
authors.lastname: Garcia
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Kilpatrick
authors.forename: Satya P
authors.initials: SP
authors.lastname: Kunapuli
mesh_terms: D000818:Animals; D015153:Blotting, Western; D039481:CD11b Antigen / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D008070:Lipopolysaccharides; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver; D009504:Neutrophils / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D000068799:Prasugrel Hydrochloride; D058919:Purinergic P2 Receptor Antagonists / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology*; D058925:Receptors, Purinergic P2Y12 / Q000187:drug effects; D013876:Thiophenes / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D039481:CD11b Antigen; D008070:Lipopolysaccharides; D010879:Piperazines; D058919:Purinergic P2 Receptor Antagonists; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes; D009195:Peroxidase; D000068799:Prasugrel Hydrochloride; D002118:Calcium