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

被引：64

作者：

Gong, Inna Y. ^{[1
,2
]}

Crown, Natalie ^{[2
]}

Suen, Colin M. ^{[2
]}

Schwarz, Ute I. ^{[1
,2
]}

Dresser, George K. ^{[1
]}

Knauer, Michael J. ^{[1
,2
]}

Sugiyama, Daisuke ^{[1
]}

DeGorter, Marianne K. ^{[1
,2
]}

Woolsey, Sarah ^{[1
,2
]}

Tirona, Rommel G. ^{[1
,2
]}

Kim, Richard B. ^{[1
,2
]}

机构：

[1] Univ Western Ontario, Schulich Sch Med & Dent, Dept Med, Div Clin Pharmacol, London, ON N6A 5A5, Canada

[2] Univ Western Ontario, Schulich Sch Med & Dent, Dept Physiol & Pharmacol, London, ON N6A 5A5, Canada

来源：

EUROPEAN HEART JOURNAL | 2012年 / 33卷 / 22期

基金：

加拿大健康研究院;

关键词：

CYP2C19; PON1; Clopidogrel; Pharmacokinetics; Pharmacogenetics; Antiplatelet response; PERCUTANEOUS CORONARY INTERVENTION; PLATELET REACTIVITY; ACTIVE METABOLITE; CLINICAL-OUTCOMES; TREATED PATIENTS; POLYMORPHISMS; PARAOXONASE-1; VARIABILITY; GENOTYPE; ASPIRIN;

D O I：

10.1093/eurheartj/ehs042

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 the mechanism and relative contribution of PON1 in comparison to CYP2C19 to clopidogrel bioactivation and antiplatelet response. First, the influence of CYP2C19 and PON1 polymorphisms and plasma paraoxonase activity on clopidogrel active metabolite (H4) levels and antiplatelet response was assessed in a cohort of healthy subjects (n 21) after administration of a single 75 mg dose of clopidogrel. There was a remarkably good correlation between H4 AUC (08 h) and antiplatelet response (r(2) 0.78). Furthermore, CYP2C19 but not PON1 genotype was predictive of H4 levels and antiplatelet response. There was no correlation between plasma paraoxonase activity and H4 levels. Secondly, metabolic profiling of clopidogrel in vitro confirmed the role of CYP2C19 in bioactivating clopidogrel to H4. However, heterologous expression of PON1 in cell-based systems revealed that PON1 cannot generate H4, but mediates the formation of another thiol metabolite, termed Endo. Importantly, Endo plasma levels in humans are nearly 20-fold lower than H4 and was not associated with any antiplatelet response. Our results demonstrate that PON1 does not mediate clopidogrel active metabolite formation or antiplatelet action, while CYP2C19 activity and genotype remains a predictor of clopidogrel pharmacokinetics and antiplatelet response.

引用

页码：2856 / U28

页数：10

共 33 条

[1] Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel [J].