کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2815895 1159900 2015 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Genetic polymorphisms of CYP2C19*2 and ABCB1 C3435T affect the pharmacokinetic and pharmacodynamic responses to clopidogrel in 401 patients with acute coronary syndrome
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی ژنتیک
پیش نمایش صفحه اول مقاله
Genetic polymorphisms of CYP2C19*2 and ABCB1 C3435T affect the pharmacokinetic and pharmacodynamic responses to clopidogrel in 401 patients with acute coronary syndrome
چکیده انگلیسی


• We provided an analysis of comprehensive genetic integrated with PD and PK response to clopidogrel in 401 patients with ACS.
• A total of 21 genes involved in various steps including absorption, metabolism, and PD of clopidogrel were studied.
• We conclude CYP2C19*2 is a key determinant for the formation of the active metabolite of clopidogrel and its PD affects.
• Meanwhile, ABCB1 polymorphisms has an important role on drug absorption which affects the exposure to the active metabolite.
• The latter is lacking in most of previously reported genetic studies.

Backgrounds and objectivesClopidogrel, an inhibitor of platelet ADP P2Y12 receptors, plays an important role in the prevention of stent thrombosis. However, some patients do not attain adequate antiplatelet effects. Studies have shown that the genetic variation in CYP2C19*2 is associated with an impaired response to clopidogrel. This study was designed to investigate the genetic variants of 21 genes involving in the absorption, metabolism, and pharmacodynamics of clopidogrel. The effects of these genes on the plasma level of clopidogrel and its metabolites (active clopi-H4 and inactive CLPM) and platelet reactivity were also studied.Methods and results401 acute coronary syndrome (ACS) patients received either a 300 mg loading dose following 75 mg maintenance dose daily or a 75 mg maintenance dose daily of clopidogrel. The inhibition of platelets was assessed using light transmittance aggregometry. Plasma concentrations of clopidogrel as well as its active (clopi-H4) and inactive (CLPM) metabolites were measured using HPLC-MS-MS method. Among 21 genes, the carriers of CYP2C19*2 were associated with lower exposure to its active (clopi-H4) and inactive (CLPM) metabolites (both P < 0.05 vs. non-carriers) and thus decreased platelet inhibition (P < 0.05 vs. non-carriers). Notably, the carriers of ABCB1 C3435T were associated with lower levels of plasma clopidogrel and its active (clopi-H4) and inactive (CLPM) metabolites (all P < 0.05 vs. non-carriers) which also correlated with subsequently decreased platelet inhibition (P < 0.05 vs. non-carriers). There were no obvious effects of other studied genes on clopidogrel.ConclusionsCYP2C19*2 is a determinant for the formation of the active metabolite of clopidogrel and its antiplatelet effects. Meanwhile, ABCB1 C3435T plays an important role in intestinal absorption of clopidogrel which further affects the exposure to the active metabolite of clopidogrel and platelet aggregation.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Gene - Volume 558, Issue 2, 10 March 2015, Pages 200–207
نویسندگان
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