MedWire News: European researchers have identified the enzyme paraoxonase-1 (PON1) as a major determinant of the bioactivation, and thus the clinical efficacy, of clopidogrel.
Using in vitro metabolomic profiling techniques, Dirk Taubert (University Maastricht, The Netherlands) and colleagues found that PON1 was crucial for the formation of the thiol active metabolite from clopidogrel, and that the Q192R polymorphism determined the rate of active metabolite formation.
"The main drawback of clopidogrel is a high interindividual variability in antiplatelet response," remark the researchers.
"Low platelet responsiveness to clopidogrel has been found to translate into a high incidence of atherothrombotic events, including stent thrombosis as the most serious and often fatal clinical event," they add.
To test the clinical relevance of the PON1 Q192R genotype, Taubert and team compared 41 coronary artery disease patients with nonfatal stent thrombosis with 71 patients without stent thrombosis.
Among these patients, PON1 QQ192 homozygous individuals showed a considerably higher risk for stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite, and lower platelet inhibition than RR192 homozygous individuals.
Indeed, heterozygous individuals who carried the QQ192 variant were 12.9 times more likely to have a definite stent thrombosis than those who carried RR192, and they were also 4.5 times more likely to have stent thrombosis than RR192 carriers.
Further evaluation of the association between PON1 and the clinical response to clopidogrel among 1982 individuals with acute coronary syndromes gave similar results. In this cohort, QQ192 carriers had a 10-fold greater risk for stent thrombosis than RR192 carriers.
Taubert and co-workers calculated that the PON1 Q192R polymorphism explained 72.5% of the variability in adenosine diphospahte-stimulated platelet aggregation after clopidogrel administration "and thus seems likely to be the primary predictor of clopidogrel response," they say.
By comparison, a common polymorphism in the cytochrome P450 2C19 gene (CYP2C19*2) accounts for only 12% of the variability.
The researchers conclude in Nature Medicine that their findings "have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel."
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