Clopidogrel (on the market as Plavix ) is an antiplatelet drug given to patients with an increased risk of thrombosis. The pill contains a prodrug, which requires further processing by the liver upon ingestion. A small subset of the population carry a genetic mutation that results in a decreased efficacy of this antiplatelet drug. 

Inactive form of clopidogrel. This molecule needs to be further modified into the active version of the drug to work efficiently as an inhibitor of the P2Y12 receptor.


a schematic of clopidogrel activation. The active metabolite of clopidogrel (upon processing) inhibits the ADP-mediated activation of the P2Y12 receptor, thereby preventing the platelets activating and aggregating.

Mechanism of antiaggregationEdit

Platelets require an ADP dependent activation. This is usually by activating a G-protein coupled receptor (GPCR) called P2Y12 receptor. The active form of clopidogrel irreversibly binds to the ligand binding site of the P2Y12 receptor, thereby preventing the binding of the natural ligand- ADP. Unactivated platelets cannot aggregate to the site of the injury, which dramatically reduces a thrombotic event cardiovasulcar disease patients. 

Drug metabolism requires Cytochrome P450Edit

Clopidogrel is a prodrug that requires further processing in the liver to yield the active form of the drug. One of the steps is an oxidation into 2-oxo-clopidogrel, mediated by Cytochrome P450. Without a functional enzyme, the inactive drug cannot be further metabolized, which lends to the reduced efficacy of the drug. 

CYP2C19 isotype and clopidogrelEdit

Cytochrome p450 has many isoforms in the liver. This enzyme catalyzes one of the crucial steps in converting  the inactive prodrug into the active form of clopidogrel. Studies have found that there are certain m

Protein CYP2C19 PDB 1r9o

A cartoon representation of Cytochrome P450, family 2, subfamily C, polypeptide 19.

utation in cytochrome p450 that correlate with a loss (or diminished) function in catalyzing the oxidation step in converting clopidogrel. There are many different mutations that have been identified that are linked to decreased clopidogrel efficacy in patients, some of which are: *2, *3, *4, *5, *6, *7, *8. Individuals with one copy of this mutated allele have are more likely to have a decreased drug response to clopidogrel, and those with two copies of the mutated allele have almost no way of metabolizing the drug to its active form, and puts them at a great risk for thrombosis.

Professor Burke is a heterozygote for the decreased clopidogrel efficacy allele- he has one normal copy (*1) and has a *2 allele, which is a loss-of-function mutation in the CYP2C19 gene. Sequencing shows an abberant stop codon inserted due to a G to A mutation, which yields a non-functional protein.1 Interestingly,  a different mutant allele (*17) leads to a gain-of-function mutation in the enzyme, which increases the efficacy of clopidogrel in individuals with this mutation. However, this may also lead to a bleeding phenotype. 

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