title: Platelet aggregometry and receptor binding to predict the magnitude of antithrombotic and bleeding time effects of clopidogrel in rabbits.
abstract: Target levels of ex vivo inhibition of platelet aggregation (IPA) induced by adenosine diphosphate (ADP) that produce clinically relevant effects of clopidogrel, a P2Y12 antagonist, are unclear. We examined standard and modified IPA and P2Y12 receptor occupancy as predictors of antithrombotic (% thrombus weight reduction) and bleeding time (BT, fold-increase over control) effects of clopidogrel in rabbit models of carotid artery thrombosis and cuticle bleeding, respectively. Standard and modified IPA with 20 microM ADP were measured in the absence and presence of partial P2Y1 blockade, respectively. Clopidogrel maximally produced standard IPA of 57% +/- 5%, antithrombotic effect of 85% +/- 1%, BT increase of 6.0 +/- 0.4-fold and P2Y12 receptor occupancy of 87% +/- 5%. Surprisingly, a clopidogrel dose that produced a low standard IPA of 17% +/- 4% and P2Y12 receptor occupancy of 39% +/- 5% achieved a significant antithrombotic activity of 55% +/- 2% with a moderate increase in BT of 2.0 +/- 0.1-fold. This underestimation of clopidogrel efficacy by standard IPA was improved by measuring either modified IPA or P2Y12 receptor occupancy. These results suggest that in clopidogrel-treated rabbits, low standard IPA is associated with significant antithrombotic effects. Moreover, modified IPA and P2Y12 receptor occupancy appear to better predict the magnitude of clopidogrel's efficacy compared with standard IPA, which may be a better predictor of BT.
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Company, Pennington, New Jersey 08534, USA. pancras.wong@bms.com
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.forename: Earl J
authors.initials: EJ
authors.lastname: Crain
authors.forename: Carol A
authors.initials: CA
authors.lastname: Watson
authors.forename: Xiaosui
authors.initials: X
authors.lastname: Jiang
authors.forename: Ji
authors.initials: J
authors.lastname: Hua
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Bostwick
authors.forename: Martin L
authors.initials: ML
authors.lastname: Ogletree
authors.forename: William A
authors.initials: WA
authors.lastname: Schumacher
authors.forename: Robert
authors.initials: R
authors.lastname: Rehfuss
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000503:physiopathology* / Q000517:prevention & control*; D017536:Carotid Artery, Common / Q000187:drug effects* / Q000503:physiopathology; D000077144:Clopidogrel; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006487:Hemostasis / Q000187:drug effects; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011237:Predictive Value of Tests; D011485:Protein Binding / Q000187:drug effects; D011817:Rabbits; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D013929:Thromboxane B2 / Q000097:blood; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D010975:Platelet Aggregation Inhibitors; D018048:Receptors, Purinergic P2; D013929:Thromboxane B2; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin