Biology and pharmacology of the platelet P2Y12 receptor

Platelets possess two receptors for ADP, P2Y(1) and P2Y(12). ADP is released from platelet dense granules upon platelet activation by numerous agonists and thereby amplifies platelet responses regardless of the initial stimulus. The P2Y(1) receptor is one of many platelet receptors coupled to Gq and initiates ADP-induced activation. The P2Y(12) receptor on the other hand is linked to Gi and plays a special role in the amplification of platelet activation initiated by numerous other pathways. Platelet activation leads to a range of responses that play a critical role in arterial thrombosis and the inflammatory responses associated with this, including platelet aggregation, dense and alpha granule secretion and procoagulant activity. P2Y(12) receptor activation yields powerful amplification of these processes such that P2Y(12) receptor antagonists may have dramatic inhibitory effects on platelet function regardless of the activating stimuli. This phenomenon, coupled with the restricted distribution of the P2Y(12) receptor in humans, makes the receptor an ideal target for pharmaceutical therapy. This has already been established by the therapeutic success of clopidogrel, which acts, via an active metabolite, on this receptor. However, current therapeutic regimens of clopidogrel yield variable and incomplete P2Y(12) receptor blockade and more effective strategies to block P2Y(12) receptor activation offer the potential of greater clinical efficacy.     

ADP receptors: inhibitory strategies for antiplatelet therapy

The interaction of adenosine-5'-diphosphate (ADP) with its platelet receptors (P2Y(1) and P2Y(12)) plays a very important role in thrombogenesis. The thienopyridine ticlopidine was the first specific antagonist of the platelet P2Y(12) ADP receptor to be tested in randomized clinical trials for the prevention of arterial thrombotic events. Although ticlopidine reduces the incidence of vascular events in patients at risk, it also unfortunately has some significant drawbacks: a relatively high incidence of toxic effects, which may be fatal in some cases; delayed onset of action; and a high interindividual variability in response. A second thienopyridine, clopidogrel, has superseded ticlopidine, because it is also an efficacious antithrombotic drug and is less toxic than ticlopidine. However, clopidogrel is not completely free from faults: severe toxic effects, albeit occurring much less frequently than with ticlopidine, may still complicate its administration to patients; the onset of pharmacologic action can be accelerated by the use of large loading doses, but may still not be optimal; the high interpatient variability in response remains an important issue. These concerns justify the continued search for agents that can further improve the clinical outcome of patients with atherosclerosis through greater efficacy and/or safety. A new thienopyridyl compound, prasugrel, which is characterized by higher potency and faster onset of action compared with clopidogrel, is currently under clinical evaluation. Two direct and reversible P2Y(12) antagonists, cangrelor and AZD6140, feature very rapid onset and reversal of platelet inhibition, which make them attractive alternatives to thienopyridines, especially when rapid inhibition of platelet aggregation or its quick reversal are required. Along with new the P2Y(12) antagonists, inhibitors of the other platelet receptor for ADP, the antagonists P2Y(1), are under development and may prove to be effective antithrombotic agents.     

血小板P2Y12受体拮抗剂临床研究进展

P2Y12受体拮抗剂是一类作用于血小板P2Y12受体、抑制血小板聚集的药物,临床上主要用于预防和治疗心血管疾病的血栓事件。氯吡格雷是目前临床上首选的双重抗血小板药物之一,但其疗效受限于CYP2C19基因的多态性、与质子泵抑制剂(PPIs)的相互作用和起效缓慢等。目前,一些新型P2Y12受体拮抗剂类抗血小板药物(如普拉格雷、替卡格雷等)已经进入临床,几项大型临床试验对其疗效和安全性进行了评价。本文对比了新型P2Y12受体拮抗剂与氯吡格雷在药理学、药代动力学、有效性和安全性方面的差异,并探讨其临床应用,为临床合理用药提供参考。     

ADP receptors--targets for developing antithrombotic agents

Platelet P2 receptors--P2Y1, P2Y12, and P2X1--constitute the means by which adenine nucleotides can activate platelets. Coactivation of the Galphaq-coupled P2Y1 and Galphai2-coupled P2Y12 receptors is necessary for ADP-mediated platelet activation, which forms the basis of using P2 antagonists as antithrombotic drugs. P2Y1 receptor antagonists inhibit platelet activation, while P2Y1 knockout mice show longer bleeding times than normal mice but few other problems; however, its ubiquitous expression in other tissues renders P2Y1 questionable as an antithrombotic target. The P2Y12 receptor is expressed nearly exclusively in platelets and brain, making it an attractive antithrombotic target. Antagonists for the P2Y12 receptor have been developed that either require metabolic activation to covalently inhibit P2Y12 and are irreversible, or simply are competitive in nature and thus reversible. Ticlopidine and clopidogrel are irreversible P2Y12 antagonists and have been repeatedly proven as clinical antithrombotic agents. In addition, a recently reported P2Y12 antagonist, CS-747, shows promise as a future antithrombotic drug. The AR-C series of compounds represent reversible P2Y12 antagonists and have been used extensively to characterize the function of P2Y12 in platelets. Clinical studies show that AR-C69931MX is as effective as clopidogrel; furthermore, the combination of AR-C69931MX (cangrelor) and clopidogrel confers greater antagonism of P2Y12 than either antagonist alone. The P2X1 receptor is a calcium channel that functions to potentiate agonist-induced platelet shape change, and its inhibition or loss has little if any effect on hemostasis. A combination of P2Y1 and P2Y12 antagonists may represent an additional course of antithrombotic treatment.     

Platelet P2Y<Subscript>12</Subscript> Receptor Inhibition

Antiplatelet therapy is the cornerstone of treatment for patients with coronary artery disease. Since adenosine diphosphate (ADP) represents one of the most important mediators of thrombosis, the inhibition of the platelet ADP receptor, in particular the P2Y₁₂ subtype, plays a pivotal role in secondary prevention of recurrent atherothrombotic events in high-risk settings. Numerous clinical trials have shown the efficacy of clopidogrel, an inhibitor of the ADP P2Y₁₂ receptor, in patients presenting with an acute coronary syndrome and undergoing percutaneous coronary intervention. However, laboratory and clinical experience with clopidogrel have led to understanding some of the limitations of this drug, the most important of which is its broad range in interindividual response variability, resulting in the development of novel ADP P2Y₁₂ receptor-inhibiting strategies. This article provides an overview of ADP P2Y₁₂ receptor-inhibiting strategies, including high clopidogrel dosing regimens and novel agents under advanced clinical development.     

Pharmacokinetic,pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases

Platelet inhibitors are the mainstay treatment for patients with vascular diseases. The current ‘gold standard’ antiplatelet agent clopidogrel has several pharmacological and clinical limitations that have prompted the search for more effective platelet antagonists. The candidates include various blockers of the purinergic P2Y12 receptor such as prasugrel, an oral irreversible thienopyridine; two adenosine triphosphate analogues that bind reversibly to the P2Y12 receptor: ticagrelor (oral) and cangrelor (intravenous); elinogrel, a direct-acting reversible P2Y12 receptor inhibitor (the only antiplatelet compound that can be administered both intravenously and orally); BX 667, an orally active and reversible small-molecule P2Y12 receptor antagonist; SCH 530348, SCH 205831, SCH 602539 and E5555, highly selective and orally active antagonists on the protease-activated receptor 1. A number of drugs also hit new targets: terutroban, an oral, selective and specific inhibitor of the thromboxane receptor; ARC1779, a second-generation, nuclease resistant aptamer which inhibits von Willebrand factor-dependent platelet aggregation; ALX-0081, a bivalent humanized nanobody targeting the GPIb binding site of von Willebrand factor and AJW200, an IgG4 monoclonal antibody of von Willebrand factor. The pharmacology and clinical profiles of new platelet antagonists indicate that they provide more consistent, more rapid and more potent platelet inhibition than agents currently used. Whether these potential advantages will translate into clinical advantages will require additional comparisons in properly powered, randomized, controlled trials.     

P2Y receptor antagonists in thrombosis

The dual role of P2Y1 and P2Y12 receptors in platelet aggregation by ADP has been firmly established, based on the action of selective inhibitors, gene targeting in mice and human genetic evidence. Both of these receptor subtypes constitute targets for antithrombotic agents, and compounds with a dual action might also be of interest. However, the agents currently on the market (ticlopidine and clopidogrel), or known to be in development (cangrelor, AZD-6140 and prasugrel), all target the P2Y12 receptor. The thienopyridines (ticlopidine, clopidogrel and prasugrel) irreversibly inactivate the P2Y12 receptor via the covalent binding of an active metabolite generated in the liver, while the other compounds are competitive antagonists. Cangrelor, an ATP derivative, is suitable for intravenous perfusion, whereas AZD-6140 is in clinical development as an orally active agent.     

AZD6140

Oral antiplatelet therapy with P2Y(12) receptor blockers (especially clopidogrel) is the current choice of treatment during acute coronary syndromes and percutaneous interventions. To address the various limitations of thienopyridine therapy (including response variability and non-responsiveness) a novel drug, AZD6140, is under clinical development. AZD6140 is an oral and reversible P2Y(12) receptor blocker that does not require hepatic conversion to an active metabolite and produces an overall superior ADP-induced platelet inhibition with less response variability than clopidogrel. It has fast onset and offset actions that may be advantageous in patients who may have to undergo immediate surgery.     

Comparative pharmacokinetics and pharmacodynamics of platelet adenosine diphosphate receptor antagonists and their clinical implications

Over the last two decades or more, anti-platelet therapy has become established as a cornerstone in the treatment of patients with ischaemic cardiovascular disease, since such drugs effectively reduce arterial thrombotic events. The original agent used in this context was aspirin (acetylsalicylic acid) but, with the advent of adenosine diphosphate (ADP) receptor antagonists, the use of dual anti-platelet therapy has resulted in further improvement in cardiovascular outcomes when compared with aspirin alone. The first group of platelet ADP receptor antagonists to be developed was the thienopyridine class, which comprise inactive pro-drugs that require in vivo metabolism to their active metabolites before exerting their inhibitory effect on the P2Y(12) receptor. Clopidogrel has been the principal ADP receptor antagonist in use over the past decade, but is limited by variability in its in vivo inhibition of platelet aggregation (IPA). The pharmacokinetics of clopidogrel are unpredictable due to their vulnerability to multiple independent factors including genetic polymorphisms. Expression of the 3435T/T genetic variant encoding the MDR1 gene for the P-glycoprotein efflux transporter results in a significantly reduced maximum drug concentration and area under the plasma concentration-time curve as intestinal absorption of clopidogrel is reduced; and the expression of the mutant *2 allele of CYP2C19 results in similar pharmacokinetic effects as the two cytochrome P450 (CYP)-mediated steps required for the production of the active metabolite of clopidogrel are impaired. These variable pharmacokinetics lead to erratic pharmacodynamics and cannot reliably be overcome with increased dosing. Both prasugrel, a third-generation thienopyridine, and ticagrelor, a cyto-pentyl-triazolo-pyrimidine, have more predictable pharmacokinetics and enhanced pharmacodynamics than clopidogrel. Neither appears to be affected by the same genetic polymorphisms as clopidogrel; prasugrel requires only a single CYP-mediated step to produce its active metabolite and ticagrelor is not a pro-drug. Enhanced IPA by both prasugrel and ticagrelor is achieved at the expense of increased major bleeding, although this is partially mitigated in the case of ticagrelor due to its reversible IPA. However, the reversible binding of ticagrelor to the P2Y(12) receptor requires a twice-daily dosing regimen. Due to limited data from clinical studies, the use of prasugrel is currently restricted to individuals undergoing percutaneous coronary intervention who are ≤75 years old and have a body weight ≥60 kg. The clinical data for ticagrelor are more comprehensive and this drug therefore has a place in the management of patients with acute coronary syndrome at moderate-to-high risk of ischaemic events, irrespective of treatment strategy. Here we review in detail the pharmacokinetics and pharmacodynamics of clopidogrel, prasugrel and ticagrelor, and explore the implications of the differences in these parameters for their clinical use.     

Prasugrel

Clinical trials have demonstrated the superior clinical efficacy of dual antiplatelet therapy with a thienopyridine (a P2Y(12) receptor blocker) and aspirin (COX-1 inhibitor) in patients undergoing stenting as well as patients with acute coronary syndromes. However, clopidogrel treatment is associated with a wide response variability and non-responsiveness in selected patients. The latter phenomenon is linked to the occurrence of recurrent ischaemic events including stent thrombosis in the recent studies. Prasugrel is a new thienopyridine derivative that produces more potent platelet inhibition and a rapid onset of action that is associated with irreversible P2Y(12) receptor blockade. The latter properties of prasugrel may provide a superior alternative to clopidogrel, with less response variability and a decreased prevalence of non-responsiveness.     

Anti-platelet therapy: ADP receptor antagonists

The P2Y(12) receptor on platelets with which ADP interacts has an important role in promoting platelet function and thereby platelet involvement in both haemostasis and thrombosis. Agents that act as antagonists at this receptor are thus likely to provide effective antithrombotic therapy, provided that there are no adverse effects on haemostasis. Here we describe the ADP receptor antagonists that are available and in development. We also consider their mode of action and ask whether there are additional mechanisms through which they exert their inhibitory effects on platelet function.     

Optimizing platelet P2Y12 inhibition for patients undergoing PCI

Guidelines recommend that dual antiplatelet therapy using aspirin and clopidogrel should be administered to the majority of patients with acute coronary syndromes, including those undergoing percutaneous coronary intervention (PCI). However, the results of a large randomized, placebo-controlled study suggest that a 300-mg loading dose of clopidogrel must be administered at least 15 h prior to PCI in order to achieve a significant reduction in peri-PCI thrombotic events. Other data suggest that 2 h of pretreatment may be sufficient if a 600-mg loading dose is used. Since it is often difficult to achieve an adequate pretreatment goal with clopidogrel in clinical practice, more rapid achievement of platelet P2Y(12) inhibition may improve patient outcomes. Prasugrel, [6-[2-(3,4-diflurophenyl) cyclopropyl1-1-y1] amino-2-propylthio-9-D-ribofuranosyl-9H-purine (AZD6140), and cangrelor are platelet P2Y(12) receptor antagonists currently in development that offer faster acting inhibition of adenosine diphosphate (ADP)--induced platelet aggregation. These agents act upon the same platelet receptor as clopidogrel, but are distinguished by their routes of administration, reversibility, and pharmacodynamic properties. Prasugrel is an orally administered agent that provides faster, higher, and more consistent inhibition of platelet aggregation than clopidogrel. The results of Phase II testing suggest that the risk of bleeding is similar in prasugrel- and clopidogrel-treated patients. AZD6140 is another orally administered platelet inhibitor with rapid and reversible action. Again, Phase II testing suggests similar bleeding risk for clopidogrel. Preliminary evidence suggests that clinical outcomes may be better in prasugrel- and AZD6140-treated patients than in clopidogrel-treated patients. Cangrelor is an intravenously administered, reversible, short-acting agent with a rapid onset of activity. Bleeding risk and clinical outcomes data are similar in cangrelor- and abciximab-treated patients. The results of ongoing Phase III clinical trials involving more than 40,000 patients will demonstrate whether these agents fulfill their potential to improve outcomes in PCI-treated patients by providing faster, higher, and more consistent inhibition of platelet aggregation.     

Platelet aggregometry and receptor binding to predict the magnitude of antithrombotic and bleeding time effects of clopidogrel in rabbits

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.     

ADP receptor antagonists as antiplatelet therapeutics

With the cloning of the P2Y12 receptor, the molecular basis for ADP-induced platelet aggregation is seemingly complete. Two platelet-bound ADP receptors, P2Y1 and P2Y12, operate through unique pathways to induce and sustain platelet aggregation via the glycoprotein (GP)IIb-IIIa integrin. P2Y1 operates via a glycoprotein q (Gq) pathway, activates phospholipase C, induces platelet shape change and is responsible for intracellular calcium mobilisation. P2Y12 inhibits adenylyl cyclase through a glycoprotein i (Gi)-dependent pathway, and is the target of the clinically used thienopyridines, ticlopidine (Ticlid, F. Hoffman-La Roche) and clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Synthelabo). In addition, the receptor is targeted by the ADP analogue AR-C66096, which is currently in Phase IIb clinical trials, as well as other non-nucleoside-based preclinical leads.     

Validation of a VerifyNow-P2Y12 cartridge for monitoring platelet inhibition with clopidogrel

Despite common use of clopidogrel in patients with vascular disease, monitoring of platelet inhibition is still not conventional in clinical practice. Considering substantial response variability, when some patients may experience inadequate protection, and/or increased risk of bleeding, simple and reliable methods to control adequate antiplatelet regimen is mandatory. We validated a new VerifyNow-P2Y12 assay to measure inhibition of the P2Y12 platelet receptors by clopidogrel by evaluating its receptor specificity, precision, and potential interference with platelet count, hematocrit, age, cholesterol, triglycerides, and other antiplatelet agents. Platelet aggregation induced by ADP or ADP + prostaglandin E1 (ADP + PGE1) in the presence of specific P2Y12 inhibitor 2-methylthio-AMP (2MeSAMP) for the assessment of assay specificity was performed in 10 volunteers. Seventeen medications were used for the VerifyNow-P2Y12 interference testing, and assay interplay with blood constituents was evaluated in a clinical setting in 131 patients with coronary artery disease. In the presence of 2MeSAMP, the average residual aggregation level across the 10 donors was 27% for ADP and 5% for ADP + PGE1. There also was a strong agreement between ADP + PGE1 aggregometry and VerifyNow-P2Y12 assay (93% vs. 95% average inhibition across all donors). The coefficient of variation for the test precision was less than 8%. The VerifyNow-P2Y12 readings were not influenced by age, platelet count, hematocrit, fibrinogen, cholesterol, or triglycerides level. There was an interference with abciximab before P2Y12 inhibition; however, after platelet suppression with cilostazol, the interference with all tested substances was minimal. VerifyNow-P2Y12 is a reliable, simple, and sensitive device suitable for monitoring of P2Y12 platelet receptor inhibitors in the clinical arena.     

Ticagrelor: a P2Y12 antagonist for use in acute coronary syndromes

Agents that inhibit platelet function are used routinely in the treatment and prevention of acute coronary syndromes. The main antiplatelet treatments used combine aspirin with one of the thienopyridine P2Y(12) antagonists, either clopidogrel or prasugrel. By blocking the synthesis of thromboxane A(2) in platelets and by blocking the effects of ADP, respectively, these agents reduce platelet activity, platelet aggregation and thrombus formation. Ticagrelor (marketed by AstraZeneca as Brilinta? in the USA, and as Brilique(?) or Possia(?) in Europe) is a cyclopentyl-triazolo-pyrimidine, a new chemical class of P2Y(12) antagonist that is now approved for use in the wide spectrum of acute coronary syndromes. In this article we provide an overview of ticagrelor. We discuss the differences in mode of action compared with other P2Y(12) antagonists, examine its pharmacodynamic, pharmacokinetic and safety profile, and summarize the various clinical trials that have provided information on its efficacy in combination with aspirin. Ticagrelor appears to overcome some of the difficulties that have been encountered with other antiplatelet treatments, clopidogrel in particular.     

Identification of a potent inverse agonist at a constitutively active mutant of human P2Y12 receptor

Human platelets express two P2Y receptors: G(q)-coupled P2Y(1), and G(i)-coupled P2Y(12). Both P2Y(1) and P2Y(12) are ADP receptors on human platelets and are essential for ADP-induced platelet aggregation that plays pivotal roles in thrombosis and hemostasis. Numerous constitutively active G protein-coupled receptors have been described in natural or recombinant systems, but in the P2Y receptors, to date, no constitutive activity has been reported. In our effort to identify G protein coupling domains of the human platelet ADP receptor, we constructed a chimeric hemagglutinin-tagged human P2Y(12) receptor with its C terminus replaced by the corresponding part of human P2Y(1) receptor and stably expressed it in Chinese hamster ovary-K1 cells. It is interesting that the chimeric P2Y(12) mutant exhibited a high level of constitutive activity, as evidenced by decreased cAMP levels in the absence of agonists. The constitutive activation of the chimeric P2Y(12) mutant was dramatically inhibited by pertussis toxin, a G(i) inhibitor. The constitutively active P2Y(12) mutant retained normal responses to 2-methylthio-ADP, with an EC(50) of 0.15 +/- 0.04 nM. The constitutively active P2Y(12) mutant caused Akt phosphorylation that was abolished by the addition of pertussis toxin. Pharmacological evaluation of several P2Y(12) antagonists revealed (E)-N-[1-[7-(hexylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d]-pyrimidin-3-yl]-1,5,6-trideoxy-beta-d-ribo-hept-5-enofuranuronoyl]-l-aspartic acid (AR-C78511) as a potent P2Y(12) inverse agonist and 5'-adenylic acid, N-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-, monoanhydride with (dichloromethylene)bis[phosphonic acid] (AR-C69931MX) as a neutral antagonist. In conclusion, this is the first report of a cell line stably expressing a constitutively active mutant of human platelet P2Y(12) receptor and the identification of potent inverse agonist.     

Platelet hyperreactivity and stent thrombosis in patients undergoing coronary stenting

Stent thrombosis (ST) is a rare but very serious event complicating percutaneous coronary intervention (PCI) procedures. Both procedure- and patient-related factors, including inadequate platelet inhibition are well known predictors of ST. According to the present guidelines, a dual antiplatelet treatment regimen consisting of aspirin and a P2Y12 receptor inhibitor such as clopidogrel, prasugrel or ticagrelor is routinely administered to ACS patients and to patients undergoing PCI in order to prevent thrombotic vessel occlusions. In recent years, evidence has grown that patients showing high on-treatment platelet reactivity (HPR) under clopidogrel intake exhibit a higher risk for the occurrence of ischemic events including ST. For assessing HPR, different platelet function assays are currently available and have already found their way into routine clinical practice in several centers. Along with this development, more potent P2Y12 receptor inhibitors like prasugrel and ticagrelor are substitutes for clopidogrel in specific circumstances such as in ACS patients or in patients who do not adequately respond to standard clopidogrel treatment. Utilizing platelet function monitoring, patients showing HPR can be identified and an optimized antiplatelet treatment regime can be tailored for these patients. This review paper aims to summarize the important facts in relation to ST and antiplatelet therapy with a particular focus on P2Y12 receptor inhibition and its ex vivo assessment in patients undergoing coronary stent placement.     

The influence of P2Y12 receptor deficiency on the platelet inhibitory activities of prasugrel in a mouse model: evidence for specific inhibition of P2Y12 receptors by prasugrel

Prasugrel is a novel orally active thienopyridine with faster, higher and more reliable inhibition of platelet aggregation than clopidogrel reflecting its metabolism in vivo to an active metabolite with selective P2Y(12) antagonistic activity. Several lines of evidence support the contention that prasugrel provides selective P2Y(12) receptor antagonistic activity. To date, however, direct evidence of P2Y(12) specific action by prasugrel in vivo is limited. In the present study, effects of prasugrel on ex vivo platelet aggregation were examined in wild type (WT) and P2Y(12)(-/-) mice. In WT mice, prasugrel showed platelet inhibition that was 8.2 times more potent than clopidogrel. In P2Y(12)(-/-) mice, ADP induced platelet aggregation was minimal, and its extent was similar to that in prasugrel-treated WT mice. In addition, no further inhibition of platelet aggregation was observed after administration of prasugrel to P2Y(12)(-/-) mice. Furthermore, prasugrel-treated WT mice showed similar aggregation patterns using collagen- and murine PAR-4 agonist peptide to those of P2Y(12)(-/-) mice treated with vehicle or prasugrel. Overall, these results clearly provide additional in vivo evidence that prasugrel has selective P2Y(12) antagonistic activity.     

Thienopyridines and Other ADP-Receptor Antagonists

Platelet P2Y12 receptor inhibition plays a pivotal role in preventing thrombotic vascular events in patients with ACS and in patients undergoing percutaneous coronary intervention (PCI). Among the P2Y12 receptor inhibitors, the group of thienopyridines include ticlopidine, clopidogrel and prasugrel, all of which are orally administered prodrugs leading to irreversible P2Y12 receptor inhibition. Non-thienopyridine derivatives including ticagrelor, cangrelor and elinogrel do not require metabolic activation and lead to a reversible P2Y12 receptor inhibition in contrast to thienopyridines. The extend of platelet inhibition is subject to the administered antiplatelet agent and influenced by individual genetic and clinical factors. Insufficient platelet inhibition, termed high platelet reactivity (HPR) is associated with an increased risk for ischemic events after PCI whereas exceeding platelet inhibition results in an increased bleeding risk. Pharmacologic properties and clinical outcome data differ substantially between the existing P2Y12 receptor inhibitors. Whether individualized antiplatelet treatment incorporating different P2Y12 receptor inhibitors improves patients' clinical outcomes warrants further investigation.