Unraveling the pharmacogenetics of clopidogrel: the paraoxonase-1 controversy.

Clarifying the importance of CYP2C19 and PON1 in the mechanism of clopidogrel bioactivation and in vivo antiplatelet response.

AIMS It is thought that clopidogrel bioactivation and antiplatelet response are related to cytochrome P450 2C19 (CYP2C19). However, a recent study challenged this notion by proposing CYP2C19 as wholly irrelevant, while identifying paraoxonase-1 (PON1) and its Q192R polymorphism as the major driver of clopidogrel bioactivation and efficacy. The aim of this study was to systematically elucidate t...

Pharmacogenetics in Practice Pharmacogenetics in Cardiology: Forays into Modern Practice

When one discusses pharmacogenetics in cardiology practice, it is almost obligatory to discuss clopidogrel. Clopidogrel is an antiplatelet used for acute coronary syndrome (ACS), percutaneous coronary intervention (PCI) with stenting, and as secondary stroke prevention in patients with aspirin allergy, among other indications. Clopidogrel is a prodrug that must be metabolized through the cytoch...

Influence of paraoxonase-1 Q192R and cytochrome P450 2C19 polymorphisms on clopidogrel response

BACKGROUND The metabolic activation of clopidogrel is a two-step process. It has been suggested that paraoxonase-1 (PON1) is a rate-limiting enzyme in the conversion of 2-oxo- clopidogrel to an active thiol metabolite. Conflicting results have been reported in regard to (1) the association of a common polymorphism of PON1 (Q192R) with reduced rates of coronary stent thrombosis in patients takin...

Paraoxonase-1 Deficiency does not Influence Clopidogrel Antiplatelet Function in Mice

Background: Clopidogrel is an antiplatelet agent used in the treatment of vascular diseases. It requires in vivo bio activation linked to the cytochrome P450. Several studies reported that paraoxonase-1 (PON1) was a crucial enzyme in clopidogrel activation, and that patients carrying a variant of the PON1192 gene polymorphism have a high risk of thrombosis. However, these reports were not confi...

Paraoxonase-1 Q192R Polymorphism and Antiplatelet Effects of Clopidogrel in Patients Undergoing Elective Coronary Stent Placement Running title: Trenk et al.; PON1 Q192R and Antiplatelet Effects of Clopidogrel