title: Which platelet function test is suitable to monitor clopidogrel responsiveness? A pharmacokinetic analysis on the active metabolite of clopidogrel.
abstract: BACKGROUND
  Multiple platelet function tests claim to be P2Y12-pathway specific and capable of capturing the biological activity of clopidogrel.
  
  
  OBJECTIVE
  The aim of the present study was to determine which platelet function test provides the best reflection of the in vivo plasma levels of the active metabolite of clopidogrel (AMC).
  
  
  METHODS
  Clopidogrel-naive patients scheduled for elective percutaneous coronary intervention (PCI) received a 600 mg loading dose of clopidogrel and 100 mg of aspirin. For pharmacokinetic analysis, blood was drawn at 0, 20, 40, 60, 90, 120, 180, 240 and 360 min after clopidogrel loading and peak plasma concentrations (C(max)) of the AMC were quantified with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Platelet function testing was performed at baseline and 360 min after the clopidogrel loading.
  
  
  RESULTS
  The VASP-assay, the VerifyNow P2Y12-assay and 20 micromol L(-1) adenosine diphosphate (ADP)-induced light transmittance aggregometry (LTA) showed strong correlations with C(max) of the AMC (VASP: R(2) = 0.56, P < 0.001; VerifyNow platelet reactivity units (PRU): R(2) = 0.48, P < 0.001; VerifyNow %inhibition: R(2) = 0.59, P < 0.001; 20 micromol L(-1) ADP-induced LTA: R(2) = 0.47, P < 0.001). Agreement with C(max) of the AMC was less evident for 5 micromol L(-1) ADP-induced LTA or whole blood aggregometry (WBA), whereas the IMPACT-R ADP test did not show any correlation with plasma levels of the AMC.
  
  
  CONCLUSIONS
  The flow cytometric VASP-assay, the VerifyNow P2Y12 assay and, although to a lesser extent, 20 micromol L(-1) ADP-induced LTA correlate best with the maximal plasma level of the AMC, suggesting these may be the preferred platelet function tests for monitoring the responsiveness to clopidogrel.
authors.affiliation: Department of Cardiology, St Antonius Hospital, Nieuwegein, the Netherlands.
authors.forename: H J
authors.initials: HJ
authors.lastname: Bouman
authors.forename: E
authors.initials: E
authors.lastname: Parlak
authors.forename: J W
authors.initials: JW
authors.lastname: van Werkum
authors.forename: N J
authors.initials: NJ
authors.lastname: Breet
authors.forename: H
authors.initials: H
authors.lastname: ten Cate
authors.forename: C M
authors.initials: CM
authors.lastname: Hackeng
authors.forename: J M
authors.initials: JM
authors.lastname: ten Berg
authors.forename: D
authors.initials: D
authors.lastname: Taubert
mesh_terms: D000244:Adenosine Diphosphate; D000368:Aged; D015906:Angioplasty, Balloon, Coronary; D001711:Biotransformation; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000097:blood; D002853:Chromatography, Liquid; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy / Q000628:therapy*; D004351:Drug Resistance; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016014:Linear Models; D008297:Male; D008840:Microfilament Proteins / Q000097:blood; D008875:Middle Aged; D010750:Phosphoproteins / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D010979:Platelet Function Tests; D011237:Predictive Value of Tests; D018048:Receptors, Purinergic P2 / Q000097:blood / Q000187:drug effects; D058925:Receptors, Purinergic P2Y12; D053719:Tandem Mass Spectrometry; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; C548576:P2RY12 protein, human; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000098662:Vasodilator-Stimulated Phosphoprotein; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine