Catapulting clopidogrel pharmacogenomics forward

  title={Catapulting clopidogrel pharmacogenomics forward},
  author={Eric J. Topol and Nicholas J. Schork},
  journal={Nature Medicine},
The antiplatelet drug clopidogrel helps prevent stent-associated thrombosis, but the antiplatelet effects are quite variable and the clinical consequences can be serious. New findings show that the variability in clopidogrel efficacy is affected by the enzyme paraoxonase-1 (PON1), which is required for clopidogrel bioactivation (pages 110–116 ). 
CD39 May Impact Clopidrogrel Pharmacodynamics
No clinically significant interaction of CYP2C19 genotype with the association of clopidogrel therapy and cardiovascular events was shown, and this explanation was confirmed by Homes MV et al.
Pharmacogenomics for the clinical nurse specialist--genetics, prescribing, and outcomes.
  • P. O'Malley
  • Biology, Medicine
    Clinical nurse specialist CNS
  • 2011
Testing in a sample of patients with coronary heart disease after stent implantation and clopidogrel therapy revealed that PON1 QQ192 homozygous persons demonstrated a significantly higher risk of stent thrombosis than RR192 persons and had lower Pon1 activity, lower plasma concentrations of metabolite, and lower platelet inhibition.
Clopidogrel Hypersensitivity: Overview of the Problem.
Clopidogrel hypersensitivity is especially problematic in patients with newly implanted drug-eluting coronary stents, and the management of clopidogsensitivity reactions is a clinical issue of great importance.
Metabolic activation of clopidogrel: in vitro data provide conflicting evidence for the contributions of CYP2C19 and PON1
Clinical evidence on the pharmacokinetic determinants of clopidogrel efficacy is summarized, and new evidence suggests that CYP-independent hydrolytic cleavage of the thioester bond may be more important than oxidative metabolism.
The effect of thienopyridines and non-thienopyridines on nitric oxide metabolism in patients with stable angina
The ability of clopidogrel and prasugrel to form RSNO is demonstrated both in vitro and in vivo, and the effect of co-administration of oral nitrates and proton pump inhibitors on NO metabolite formation was investigated, with particular emphasis on SNO bio-synthesis in-vivo.
The Basics of Antithrombotic Medications: How Do They Work and Why Should We Care?
Insight is provided into the impact of these drugs on clinical decision-making in the rehabilitation of older adults and by gaining familiarity with hemostasis and mechanisms of action of common drugs, therapists can more easily understand the adverse effects of these medications.
A Novel Multiplex HRM Assay to Detect Clopidogrel Resistance
This work involves the development of a multiplex high-resolution melting (HRM) assay to genotype all five SNPs associated with resistance to clopidogrel therapy in Chinese population in 2 tubes.


Paraoxonase-1 is a major determinant of clopidogrel efficacy
Using in vitro metabolomic profiling techniques, paraoxonase-1 (PON1) is identified as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation.
Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.
CYP2C19*2 genotype was associated with diminished platelet response to clopidogrel treatment and poorer cardiovascular outcomes, and patients with the CYP2C 19*2 variant were more likely to have a cardiovascular ischemic event or death during 1 year of follow-up.
Genetic determinants of response to clopidogrel and cardiovascular events.
Among patients with an acute myocardial infarction who were receiving clopidogrel, those carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than those who were not, particularly marked among the patients undergoing percutaneous coronary intervention.
Cytochrome p-450 polymorphisms and response to clopidogrel.
Carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers.
Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects.
The CYP2C19*2 loss-of-function allele is associated with a marked decrease in platelet responsiveness to clopidogrel in young healthy male volunteers and may therefore be an important genetic contributor to clopsinogrel resistance in the clinical setting.
The case for routine genotyping in dual-antiplatelet therapy.
Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.
Among patients treated with clopidogrel for percutaneous coronary intervention, carriage of even 1 reduced-function CYP2C19 allele appears to be associated with a significantly increased risk of major adverse cardiovascular events, particularly stent thrombosis.