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Enhanced active met...
Enhanced active metabolite generation and platelet inhibition with prasugrel compared to clopidogrel regardless of genotype in thienopyridine metabolic pathways
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- Braun, Oscar (author)
- Lund University,Lunds universitet,Kardiologi,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Cardiology,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine
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Angiolillo, Dominick J. (author)
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Ferreiro, Jose L. (author)
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Jakubowski, Joseph A. (author)
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Winters, Kenneth J. (author)
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Effron, Mark B. (author)
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Duvvuru, Suman (author)
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Costigan, Timothy M. (author)
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Sundseth, Scott S. (author)
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Walker, Joseph R. (author)
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Saucedo, Jorge F. (author)
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Kleiman, Neal S. (author)
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- Varenhorst, Christoph (author)
- Uppsala universitet,Uppsala kliniska forskningscentrum (UCR)
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(creator_code:org_t)
- 2013
- 2013
- English.
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In: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 110:6, s. 1223-1231
- Related links:
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https://doi.org/10.1...
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http://www.ncbi.nlm....
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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Abstract
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- Clopidogrel response varies according to the presence of genetic polymorphisms. The CYP2C19*2 allele has been associated with impaired response; conflicting results have been reported for CYP2C19*17, ABCB1, and PON1 genotypes. We assessed the impact of CYP2C19, PON1, and ABCB1 polymorphisms on clopidogrel and prasugrel pharmacodynamic (PD) and pharmacokinetic (PK) parameters. Aspirin-treated patients (N=194) with coronary artery disease from two independent, prospective, randomised, multi-centre studies comparing clopidogrel (75 mg) and prasugrel (10 mg) were genotyped and classified by predicted CYP2C19 metaboliser phenotype (ultra metabolisers [UM] = *17 carriers; extensive metabolisers [EM] = *1/1 homozygotes; reduced metabolisers [RM] = *2 carriers). ABCB1 T/T and C/T polymorphisms and PON1 A/A, A/G and G/G polymorphisms were also genotyped. PD parameters were assessed using VerifyNow (R) P2Y12 and vasodilator stimulated phosphoprotein (VASP) expressed as platelet reactivity index (PR!) after 14 days of maintenance dosing. Clopi-, dogrel and prasugrel active metabolite (AM) exposure was calculated in a cohort of 96 patients. For clopidogrel, genetic variants in CYP2C19, but notABCB1 or PON1, affected PK and PD. For prasugrel, none of the measured genetic variants affected PK or PD. Compared with clopidogrel, platelet inhibition with prasugrel was greater even in the CYP2C19 UM phenotype. Prasugrel generated more AM and achieved greater platelet inhibition than clopidogrel irrespective of CYP2C19, ABCB1, and PON1 polymorphisms. The lack of effect from genetic variants on prasugrel AM generation or antiplatelet activity is consistent with previous studies in healthy volunteers and is consistent with improved efficacy in acute coronary syndrome patients managed with percutaneous coronary intervention.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Keyword
- Clopidogrel
- prasugrel
- CYP2C19
- PON1
- ABCB1
- platelet function
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Braun, Oscar
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Angiolillo, Domi ...
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Ferreiro, Jose L ...
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Jakubowski, Jose ...
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Winters, Kenneth ...
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Effron, Mark B.
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show more...
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Duvvuru, Suman
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Costigan, Timoth ...
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Sundseth, Scott ...
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Walker, Joseph R ...
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Saucedo, Jorge F ...
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Kleiman, Neal S.
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Varenhorst, Chri ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cardiac and Card ...
- Articles in the publication
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Thrombosis and H ...
- By the university
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Uppsala University
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Lund University