Wednesday, July 13, 2011

Contradictory findings on PON-1 and clopidogrel responsiveness

An example of how knowledge progresses in fits and starts:

Clopidogrel is an anti-platelet drug used to prevent clotting, which can cause heart attack or stroke. Some people are not responsive to the drug - so researchers have explored genetic mutations that may alter the enzymes involved in its activation. The cytochrome P450 enzymes have been of particular interest because of their role in drug metbolism.

However, other research surprisingly identified PON-1 (paraoxanase-1) as being involved in clopidogrel's metabolism. Then research found that the mutation of interest wasn't actually associated with responsiveness. They did, however, confirm the CYP (cytochrome P450) enzyme mutations.

    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 cytochrome P450 (CYP), which consists of various forms and subtypes denoted successively by numbers, letters, and numbers.

Clopidogrel was once commonly prescribed alongside atorvastatin (brand name: Lipitor), a CYP3A4 substrate, but atorvastatin appeared to inihibit 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 Nature Medicine in December 2010 to be crucial to the processing of clopidogrel to an active metabolite in patients with coronary artery disease who received anti-platelet therapy after stent placement (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. treatment response). The original study was likely too small to find true differences in the presence of PON-1 Q192R according to analysis at Heartwire. Another study published in Circulation: Cardiovascular Genetics in June 2011 confirms 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.

These results do not rule out a role of PON-1 in the metabolic pathway, but CYP enzymes still appear to be more important to the bioactivation of the drug. A blood test to predict a treatment response is still a long way off.

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