Genetics
Chemical structure of the anti-platelet drug clopidogrel

Contradictory research on the association between PON-1 and clopidogrel responsiveness



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Chemical structure of the anti-platelet drug clopidogrel
Alicia M Prater PhD's image for:
"Contradictory research on the association between PON-1 and clopidogrel responsiveness"
Caption: Chemical structure of the anti-platelet drug clopidogrel
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Image by: FredtheOyster, Wikimedia
© Public Domain, released http://commons.wikimedia.org/wiki/File:Clopidogrel_active_metabolite.svg

Clopidogrel is the generic name for an anti-platelet drug used to prevent heart attack and stroke. It is sold under the brand name Plavix. In order for the drug to work, it must be metabolized in the body. Metabolic enzymes are encoded by genes, making drug metabolism susceptible to genetic variation due to mutation. The common drug metabolism system is the cytochrome P450 (CYP) system, which consists of various forms and subtypes denoted successively by numbers, letters, numbers.

Clopidogrel was once commonly prescribed alongside atorvastatin (brand name: Lipitor), a CYP3A4 substrate, but atorvastatin appeared to inhibit the anti-platelet effects of Plavix. In 2003, CYP3A4 and 3A5 were shown to be involved in the metabolism of clopidogrel, indicating that atorvastatin may compete for enzyme with clopidogrel. Since that time, many other CYP variants have been associated with the metabolic pathway involved in activation of the drug. There was some controversy in late 2010 when researchers described another enzyme as being the important bioactivator – paraoxonase-1.

Paraoxonase-1 is encoded by the PON-1 gene. A mutation in this gene, known as Q192R, was reported in the journal Nature Medicine in December 2010 to be crucial to the processing of clopidogrel into an active metabolite in patients with coronary artery disease who received anti-platelet therapy after stent placement (the treatment is given to avoid clots). The European Consortium that published the results hoped it would open the door to a blood test to determine whether a patient would respond to treatment prior to pursuing it. Variation in the PON-1 gene, including Q192R, was considered by the study authors to explain 70 percent of variability in the clopidogrel response seen among patients.

Just one problem – further research has refuted these findings. A study published in the European Heart Journal in April 2011 showed no effect of PON-1 Q192R on clopidogrel activation; instead, the CYP2C19*2 variant, another form of the P450 enzymes, was associated with bioactivation and anti-platelet effects (i.e. a treatment response). The original study was likely too small to find true differences in the presence of PON-1 Q192R, according to an analysis at Heartwire. Another study published in Circulation: Cardiovascular Genetics in June 2011 confirmed the findings of the April study, which refuted the December 2010 findings – PON-1 Q192R had no effect on the anti-platelet effects of clopidogrel treatment in patients undergoing stent placement.

A 2012 study in Clinical Pharmacology and Therapeutics also refuted a connection between PON-1 and cardiovascular events, but confirmed the association with CYP2C19. However, a 2013 study refuted the CYP2C19 association in a specific population (Malaysia) - but they were healthy volunteers, so the prediction of cardiovascular events recurring could not be tested.

These results do not rule out a role of the PON-1 gene in the metabolic pathway, but based on the research the CYP enzymes still appear to be more important to the bioactivation of the drug. Because of the variability in the findings, a blood test to predict a treatment response to Plavix and other clopidogrel drugs after a cardiovascular event is still a long way off.

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