Pharmacogenetics in Cardiovascular Antithrombotic Therapy
Francisco Marín, MD, PhD*,
Rocío González-Conejero, PhD ,
Piera Capranzano, MD ,
Theodore A. Bass, MD,
Vanessa Roldán, MD, PhD and
Dominick J. Angiolillo, MD, PhD,*
* Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
Centro de Hemodonación, Universidad de Murcia, Murcia, Spain
Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida
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Figure 1 Genetic Targets Potentially Modulating Clopidogrel-Induced Antiplatelet Effects
Clopidogrel is a pro-drug that, after intestinal absorption, is metabolized in the liver by cytochrome (P450 CYP) system to generate an active metabolite. The active metabolite then irreversibly inhibits the platelet P2Y12 receptor, which in turn blocks platelet activation and subsequent aggregation ultimately mediated by the glycoprotein (GP) IIb/IIIa receptor. Genetic polymorphisms of targets in this metabolic pathway may all potentially influence clopidogrel-induced antiplatelet effects. Of these, the genetic variations of CYP enzymes, in particular 2C19, which is involved in both metabolic steps and strongly modulates the generation of clopidogrel's active metabolite, seem to be the most important. MDR = multidrug resistance-associated protein.
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Figure 2 Vitamin K Cycle
The vitamin K cycle regenerates the reduced form of vitamin K from its epoxide form through the vitamin K epoxide reductase (VKOR). Reduced vitamin K is necessary for post-translational gamma-carboxylation of glutamic acid residues of the vitamin K-dependent coagulation factors FII, FVII, FIX, and FX and proteins C, S, and Z. Gamma-carboxylation is catalyzed by a gamma-glutamyl carboxylase and requires the reduced form of vitamin K, molecular oxygen, and carbon dioxide. Vitamin K antagonists (VKAs) produce their anticoagulant effect, interfering with VKOR activity.
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