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Resistance to clopidogrel: A review of the evidence

Thuy Anh Nguyen, MSc, Pharm^_*, Jean G. Diodati, MD^,,|| and Chantal Pharand, PharmD^_*,,,_*

^_* Pharmacy Department, Hôpital du Sacré-Coeur de Montréal, Montreal, Canada
Service of Cardiology, Hôpital du Sacré-Coeur de Montréal, Montreal, Canada
Research Centre, Hôpital du Sacré-Coeur de Montréal, Montreal, Canada
Faculty of Pharmacy, Université de Montréal, Montreal, Canada.
^|| Faculty of Medicine, Université de Montréal, Montreal, Canada.

View larger version (29K): [in a new window]   Figure 1 Mechanism of action of clopidogrel. Clopidogrel competitively and irreversibly inhibits the adenosine diphosphate (ADP) P2Y12 receptor; ADP binds to the P2Y1 receptor to induce change in platelet shape and a weak and transient platelet aggregation. The binding of ADP to its Gi-coupled P2Y12 receptor liberates the Gi protein subunits Gi and ß. The subunit Gi leads to the inhibition of adenylyl cyclase (AC), which, in turn, lowers the cyclic adenosine monophosphate (cAMP) level. This inhibits the cAMP-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) (VASP-P), which is known to be closely related to the inhibition of glyprotein IIb/IIIa receptor activation. The subunit ß activates the phosphatidylinositol 3-kinase (PI3K), which potentiates dense- and -granule secretion. Multiple arrows within a given pathway indicate that intermediate steps may be involved. Dotted arrows indicate inhibition, whereas solid arrows represent activation. CYP450 = cytochrome P450; PGE1 = prostaglandin E1; PKA = protein kinase activation; PLC = phospholipase C.