Clopidogrel is a pro-drug administered orally. Approximately 85% of the pro-drug is hydrolyzed by esterases in the blood to an inactive carboxylic acid derivative, and only 15% of the pro-drug is metabolized by the cytochrome P450 (CYP) system in the liver to generate an active metabolite. The active metabolite irreversibly inhibits the adenosine diphosphate (ADP) P2Y₁₂ receptor. Activation of the P2X₁ and P2Y₁ receptors leads to alteration in shape and initiates a weak and transient phase of platelet aggregation. The P2X₁ mediates extracellular calcium influx and utilizes adenosine triphosphate (ATP) as an agonist. The binding of ADP to the G_q-coupled P2Y₁ receptor leads to activation of phospholipase C (PLC), which generates diacylglycerol (DAG) and inositol triphosphate (IP3) from phosphatidylinositol bisphosphate (PIP2). Diacylglycerol activates protein kinase C (PKC) leading to phosphorylation of myosin light chain kinase (MLCK-P); IP3 leads to mobilization of intracellular calcium. The P2Y₁ receptor is coupled to another G-protein, G₁₂, which activates the "Rho" protein and is believed to lead to change in platelet shape. The binding of ADP to the G_i-coupled P2Y₁₂ receptor liberates the G_i protein subunits _i and ß and results in stabilization of platelet aggregation. The _i subunit leads to inhibition of adenylyl cyclase (AC), which reduces cyclic adenosine monophosphate (cAMP) levels. This, in turn, diminishes cAMP-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) (VASP-P). The status of VASP-P modulates glycoprotein (GP) IIb/IIIa receptor activation. The subunit ß activates the phosphatidylinositol 3-kinase (PI3K), which leads to GP IIb/IIIa receptor activation through activation of a serine-threonine protein kinase B (PKB/Akt) and of Rap1b GTP binding proteins. Prostaglandin E₁ (PGE₁) activates AC, which increases cAMP levels and status of VASP-P. Solid arrows = activation; dotted arrows = inhibition.

Platelet aggregation profile (maximal 20 µmol/l ADP-induced platelet aggregation using light transmittance aggregometry) in patients (n = 135) in a steady state phase (>1 month) of combined aspirin (100 mg/day) and clopidogrel (75 mg/day) therapy. Heterogeneous antiplatelet effects are observed in the overall patient population as depicted by the normal bell-shaped distribution of platelet aggregation. ADP = adenosine diphosphate (D.J. Angiolillo, unpublished data, 2006).

ADP = adenosine diphosphate; CYP = cytochrome P450; GP = glycoprotein.