title: The reversible P2Y antagonist cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to produce irreversible inhibition of platelet function.
abstract: BACKGROUND
  Agents that act as antagonists at P2Y(12) ADP receptors on platelets are in use (clopidogrel), and in development for use (cangrelor and prasugrel), in patients with cardiovascular disease. Cangrelor is a direct-acting reversible antagonist being developed for short-term infusion; clopidogrel and prasugrel are oral prodrugs that provide irreversible inhibition via transient formation of active metabolites. At the cessation of cangrelor infusion, patients are likely to receive clopidogrel or prasugrel as a means of maintaining antiplatelet therapy.
  
  
  OBJECTIVE
  To apply an experimental in vitro approach to investigate the possibility that cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to inhibit ADP-mediated platelet function.
  
  
  METHODS
  The effects of cangrelor and the active metabolites of clopidogrel (C-AM) and prasugrel (P-AM) on platelet function were assessed by ADP-induced platelet P-selectin expression in whole blood. The method involved rapid removal of the antagonists by dilution, and measurement of residual platelet inhibition.
  
  
  RESULTS
  Cangrelor, C-AM and P-AM markedly inhibited P-selectin expression. The effect of cangrelor, but not of C-AM and P-AM, was reversible following antagonist removal. Preincubation of blood with cangrelor prior to addition of C-AM or P-AM reduced the ability of metabolites to irreversibly antagonize P2Y(12). Irreversible inhibition was maintained when blood was preincubated with metabolites prior to cangrelor.
  
  
  CONCLUSIONS
  Cangrelor influences the ability of the active metabolites of clopidogrel or prasugrel to inhibit platelet function irreversibly. Careful consideration should be given to the timing of administration of an oral P2Y(12) antagonist following cangrelor infusion.
authors.affiliation: Cardiovascular Medicine, University of Nottingham, Nottingham, UK. msxnld@nottingham.ac.uk
authors.forename: N L
authors.initials: NL
authors.lastname: Dovlatova
authors.forename: J A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: A
authors.initials: A
authors.lastname: Sugidachi
authors.forename: S
authors.initials: S
authors.lastname: Heptinstall
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects; D002478:Cells, Cultured; D000077144:Clopidogrel; D004347:Drug Interactions; D006801:Humans; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors; D010979:Platelet Function Tests; D000068799:Prasugrel Hydrochloride; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes / Q000378:metabolism / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: C548576:P2RY12 protein, human; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; C117446:cangrelor; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine