Figure 1.

Clopidogrel is an orally administered pro-drug. In the liver, approximately 15% of absorbed clopidogrel is metabolized by the cytochrome P450 (CYP) system to generate its active metabolite via a 2-step bioactivation process, whereas the rest 85% is hydrolyzed by carboxylesterase 1 (CES1) to an inactive carboxylic acid derivative. CES1 also catalyzes the hydrolysis of the intermediate metabolite 2-oxo-clopidogrel and the active metabolite. The active metabolite binds to the adenosine diphosphate (ADP) P2Y₁₂ receptor on the surface of platelet and leads to an irreversible inhibition of platelet aggregation. ADP binds to the G_q-coupled P2Y₁ receptor, which activates phospholipase C (PLC) that forms inositol triphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol bisphosphate (PIP2). IP3 causes mobilization of intracellular calcium, whereas DAG activates protein kinase C (PKC) and leads to phosphorylation of myosin light chain kinase (MLCK-P). These two processes both lead to initiation of platelet aggregation. On the other hand, activation of P2Y₁ receptor coupled G₁₂, another G-protein, which activates the “Rho” protein, as well as activation of P2X₁ receptor by adenosine triphosphate (ATP), which causes extracellular calcium influx, both lead to change of platelet shape. Activation of the Gi-coupled P2Y₁₂ receptor by ADP leads to release of the α_i and β_γ subunits, which ultimately lead to stabilization of platelet aggregation. The α_i subunit inhibits adenylyl cyclase (AC), which decreases intracellular levels of cyclic adenosine monophosphate (cAMP), reduces cAMP-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) (VASP-P), and modulates activation of glycoprotein (GP) IIb/IIIa receptor. The β_γ subunit activates the phosphatidylinositol 3-kinase (PI3K), which in turn, cause activation of a serine-threonine protein kinase B (PKB/Akt) and of Rap1b GTP binding proteins and causes activation of GP IIb/IIIa receptor. In addition, Prostaglandin E₁ (PGE₁) elevates cAMP and VASP-P levels via activation of AC. Solid arrows represent activation, dashed arrows represent inhibition (This figure is modified from Angiolillo, DJ et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. Am Coll Cardiol. 2007 Apr 10;49(14):1505–16 [3]).