Influence of paraoxonase-1 Q192R and cytochrome P450 2CI9 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 comm...

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Bibliographic Details
Published in:Clinical pharmacology: advances and applications 2012-01, Vol.4, p.13
Main Authors: Kreutz, Rolf P, Nystrom, Perry, Kreutz, Yvonne, Miao, Jia, Desta, Zeruesenay, Breall, Jeffrey A, Li, Lang, Chiang, ChienWei, Kovacs, Richard, Flockhart, David A, Jin, Yan
Format: Article
Language:English
Subjects:
Clopidogrel
Cytochrome P-450
Genetic aspects
Health aspects
Single nucleotide polymorphisms
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Summary: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 taking clopidogrel and (2) its effects on platelet inhibition in patient populations of European descent. Methods: Blood samples from 151 subjects of mixed racial background with established coronary artery disease and who received clopidogrel were analyzed. Platelet aggregation was determined with light transmittance aggregometry and VerifyNow® P2Y12 assay. Genotyping for cytochrome P450 2C19 (CYP2C19) * 2 and * 3 and PON1 (Q192R) polymorphisms was performed. Results: Carriers of CYP2C19*2 alleles exhibited lower levels of platelet inhibition and higher on-treatment platelet aggregation than noncarriers. There was no significant difference in platelet aggregation among PON1 Q192R genotypes. Homozygous carriers of the wild-type variant of PON1 (QQ192) had similar on-treatment platelet reactivity to carriers of increased-function variant alleles during maintenance clopidogrel dosing, as well as after administration of a clopidogrel 600 mg loading dose. Conclusion: CYP2C19*2 allele is associated with impaired platelet inhibition by clopidogrel and high on-treatment platelet aggregation. PON1 (Q192R) polymorphism does not appear to be a significant determinant of clopidogrel response. Keywords: PON1, platelet, aggregation, cytochrome P450 enzymes
ISSN:1179-1438
1179-1438
DOI:10.2147/CPAA.S27822