**7.2. Clopidogrel**

The obvious candidates for pharmacogenetic analysis are genes involved in clopidogrel me‐ tabolism. Clopidogrel is a prodrug and its active form, thiol, is formed during the biotrans‐ formation in the liver. CYP2C19, CYP3A4/5, CYP1A2, and CYP2B6 are involved in this process [142].

P2Y12 belongs to the G protein-coupled purinergic receptor for adenosine diphosphate (ADP). The P2Y12 protein is found mainly, but not exclusively, on the surface of blood pla‐ telets, and is an important regulator in blood clotting. The active clopidogrel metabolite irre‐ versibly binds to platelet ADP P2Y12 receptors. ADP P2Y12 receptors and loss-of-function CYP2C19\*2 was identified as the single major genetic determinant of biochemical response to clopidogrel, accounting for approximately 12% of the variation in ADP-stimulated plate‐ let aggregation during drug treatment [143]. CYP2C19\*2 carriers treated with clopidogrel have an increased risk for major adverse cardiovascular events compared to noncarriers and increased risks of stent thrombosis [144].

Loss-of-function CYP2C19\*2 allele has been reproducibly shown to be associated with a de‐ creased conversion of clopidogrel into its active metabolite, reduced antiplatelet effect and increased risk for cardiovascular events in patients using clopidogrel [4, 145].

The frequency of CYP2C19\*2 polymorphism varies in different populations: in Caucasian, African American, and Mexicans it presence is 18% to 33% (2%–3% homozygotes) and the allele frequency is higher in Asians. The loss-of-function \*3 variant is also associated with poorer response and is highly prevalent in Asians [146, 147].

P-glycoprotein, also known as multidrug resistance protein 1 (MDR1) or ATP-binding cas‐ sette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243), is a glyco‐ protein that in humans is encoded by the ABCB1 gene. ABC transporters are transmembrane proteins that utilize the energy of adenosine triphosphate hydrolysis to car‐ ry out certain biological processes including translocation of various substrates across mem‐ branes and non-transport-related processes such as translation of RNA and DNA repair. Contradicting results have been reported for variants in ABCB1 and Gln192Arg allele in par‐ aoxonase 1, which have been implicated in clopidogrel responsiveness. These associations need further confirmation [148-150].
