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

Rolf P Kreutz1,2, Perry Nystrom2, Yvonne Kreutz2, Jia Miao2, Zeruesenay Desta2, Jeffrey A Breall1, Lang Li2, ChienWei Chiang2, Richard Kovacs1, David A Flockhart2, Yan Jin21Krannert Institute of Cardiology, 2Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN,...

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Autores principales:	Li L, Breall JA, Desta Z, Miao J, Kreutz Y, Nystrom P, Kreutz RP, Chiang C, Kovacs R, Flockhart DA, Jin Y
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2012
Materias:	Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/1893841e84934beda5891b901b5f6be4
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spelling	oai:doaj.org-article:1893841e84934beda5891b901b5f6be42021-12-02T00:56:29ZInfluence of paraoxonase-1 Q192R and cytochrome P450 2C19 polymorphisms on clopidogrel response1179-1438https://doaj.org/article/1893841e84934beda5891b901b5f6be42012-02-01T00:00:00Zhttp://www.dovepress.com/influence-of-paraoxonase-1-q192r-and-cytochrome-p450-2c19-polymorphism-a9301https://doaj.org/toc/1179-1438Rolf P Kreutz1,2, Perry Nystrom2, Yvonne Kreutz2, Jia Miao2, Zeruesenay Desta2, Jeffrey A Breall1, Lang Li2, ChienWei Chiang2, Richard Kovacs1, David A Flockhart2, Yan Jin21Krannert Institute of Cardiology, 2Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USABackground: 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&reg; P2Y12 assay. Genotyping for cytochrome P450 2C19 (CYP2C19)2 and 3 and PON1 (Q192R) polymorphisms was performed.Results: Carriers of CYP2C192 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: CYP2C192 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 enzymesLi LBreall JADesta ZMiao JKreutz YNystrom PKreutz RPChiang CKovacs RFlockhart DAJin YDove Medical PressarticleTherapeutics. PharmacologyRM1-950ENClinical Pharmacology: Advances and Applications, Vol 2012, Iss default, Pp 13-20 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950
spellingShingle	Therapeutics. Pharmacology RM1-950 Li L Breall JA Desta Z Miao J Kreutz Y Nystrom P Kreutz RP Chiang C Kovacs R Flockhart DA Jin Y Influence of paraoxonase-1 Q192R and cytochrome P450 2C19 polymorphisms on clopidogrel response
description	Rolf P Kreutz1,2, Perry Nystrom2, Yvonne Kreutz2, Jia Miao2, Zeruesenay Desta2, Jeffrey A Breall1, Lang Li2, ChienWei Chiang2, Richard Kovacs1, David A Flockhart2, Yan Jin21Krannert Institute of Cardiology, 2Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USABackground: 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&reg; P2Y12 assay. Genotyping for cytochrome P450 2C19 (CYP2C19)2 and 3 and PON1 (Q192R) polymorphisms was performed.Results: Carriers of CYP2C192 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: CYP2C192 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
format	article
author	Li L Breall JA Desta Z Miao J Kreutz Y Nystrom P Kreutz RP Chiang C Kovacs R Flockhart DA Jin Y
author_facet	Li L Breall JA Desta Z Miao J Kreutz Y Nystrom P Kreutz RP Chiang C Kovacs R Flockhart DA Jin Y
author_sort	Li L
title	Influence of paraoxonase-1 Q192R and cytochrome P450 2C19 polymorphisms on clopidogrel response
title_short	Influence of paraoxonase-1 Q192R and cytochrome P450 2C19 polymorphisms on clopidogrel response
title_full	Influence of paraoxonase-1 Q192R and cytochrome P450 2C19 polymorphisms on clopidogrel response
title_fullStr	Influence of paraoxonase-1 Q192R and cytochrome P450 2C19 polymorphisms on clopidogrel response
title_full_unstemmed	Influence of paraoxonase-1 Q192R and cytochrome P450 2C19 polymorphisms on clopidogrel response
title_sort	influence of paraoxonase-1 q192r and cytochrome p450 2c19 polymorphisms on clopidogrel response
publisher	Dove Medical Press
publishDate	2012
url	https://doaj.org/article/1893841e84934beda5891b901b5f6be4
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Influence of paraoxonase-1 Q192R and cytochrome P450 2C19 polymorphisms on clopidogrel response

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