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Research ArticleInflammation, Immunopharmacology, and Asthma

Prasugrel Metabolites Inhibit Neutrophil Functions

Elisabetta Liverani, Mario C. Rico, Analia E. Garcia, Laurie E. Kilpatrick and Satya P. Kunapuli
Journal of Pharmacology and Experimental Therapeutics January 2013, 344 (1) 231-243; DOI: https://doi.org/10.1124/jpet.112.195883
Elisabetta Liverani
Sol Sherry Thrombosis Research Center (E.L., M.C.R., A.E.G., L.E.K., S.P.K.), Department of Physiology (L.E.K., S.P.K.), and Temple Lung Center (L.E.K), Temple University School of Medicine, Temple University Hospital, Philadelphia, Pennsylvania
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Mario C. Rico
Sol Sherry Thrombosis Research Center (E.L., M.C.R., A.E.G., L.E.K., S.P.K.), Department of Physiology (L.E.K., S.P.K.), and Temple Lung Center (L.E.K), Temple University School of Medicine, Temple University Hospital, Philadelphia, Pennsylvania
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Analia E. Garcia
Sol Sherry Thrombosis Research Center (E.L., M.C.R., A.E.G., L.E.K., S.P.K.), Department of Physiology (L.E.K., S.P.K.), and Temple Lung Center (L.E.K), Temple University School of Medicine, Temple University Hospital, Philadelphia, Pennsylvania
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Laurie E. Kilpatrick
Sol Sherry Thrombosis Research Center (E.L., M.C.R., A.E.G., L.E.K., S.P.K.), Department of Physiology (L.E.K., S.P.K.), and Temple Lung Center (L.E.K), Temple University School of Medicine, Temple University Hospital, Philadelphia, Pennsylvania
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Satya P. Kunapuli
Sol Sherry Thrombosis Research Center (E.L., M.C.R., A.E.G., L.E.K., S.P.K.), Department of Physiology (L.E.K., S.P.K.), and Temple Lung Center (L.E.K), Temple University School of Medicine, Temple University Hospital, Philadelphia, Pennsylvania
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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 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 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 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 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 P2Y12 or P2Y13 receptor in neutrophils.

Footnotes

  • This research was supported by the National Institutes of Health [Grants K01-HL092586 (to A.E.G.), T32-HL07777 and K01-HL103197 (to M.C.R.), and HL60683 and HL93231 (to S.P.K.)].

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • dx.doi.org/10.1124/jpet.112.195883.

  • Received April 30, 2012.
  • Accepted October 23, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 1
1 Jan 2013
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Research ArticleInflammation, Immunopharmacology, and Asthma

Prasugrel Metabolites' Effect on Neutrophils

Elisabetta Liverani, Mario C. Rico, Analia E. Garcia, Laurie E. Kilpatrick and Satya P. Kunapuli
Journal of Pharmacology and Experimental Therapeutics January 1, 2013, 344 (1) 231-243; DOI: https://doi.org/10.1124/jpet.112.195883

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Research ArticleInflammation, Immunopharmacology, and Asthma

Prasugrel Metabolites' Effect on Neutrophils

Elisabetta Liverani, Mario C. Rico, Analia E. Garcia, Laurie E. Kilpatrick and Satya P. Kunapuli
Journal of Pharmacology and Experimental Therapeutics January 1, 2013, 344 (1) 231-243; DOI: https://doi.org/10.1124/jpet.112.195883
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