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Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease.
- Source :
-
European heart journal [Eur Heart J] 2009 Jul; Vol. 30 (14), pp. 1744-52. Date of Electronic Publication: 2009 May 09. - Publication Year :
- 2009
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Abstract
- Aims: The metabolic pathways leading to the formation of prasugrel and clopidogrel active metabolites differ. We hypothesized that decreased CYP2C19 activity affects the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel.<br />Methods and Results: Ninety-eight patients with coronary artery disease (CAD) taking either clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD were genotyped for variation in six CYP genes. Based on CYP genotype, patients were segregated into two groups: normal function (extensive) metabolizers (EM) and reduced function metabolizers (RM). Plasma active metabolite concentrations were measured at 30 min, 1, 2, 4, and 6 h post-LD and during the MD period on Day 2, Day 14, and Day 29 at 30 min, 1, 2, and 4 h. Vasodilator-stimulated phosphoprotein (VASP) and VerifyNow P2Y12 were measured predose, 2, and 24 +/- 4 h post-LD and predose during the MD period on Day 14 +/- 3 and Day 29 +/- 3. For clopidogrel, active metabolite exposure was significantly lower (P = 0.0015) and VASP platelet reactivity index (PRI, %) and VerifyNow P2Y(12) reaction unit (PRU) values were significantly higher (P < 0.05) in the CYP2C19 RM compared with the EM group. For prasugrel, there was no statistically significant difference in active metabolite exposure or pharmacodynamic response between CYP2C19 EM and RM. Variation in the other five genes demonstrated no statistically significant differences in pharmacokinetic or pharmacodynamic responses.<br />Conclusion: Variation in the gene encoding CYP2C19 in patients with stable CAD contributes to reduced exposure to clopidogrel's active metabolite and a corresponding reduction in P2Y(12) inhibition, but has no significant influence on the response to prasugrel.
- Subjects :
- Clopidogrel
Coronary Disease drug therapy
Coronary Disease genetics
Cytochrome P-450 CYP2C19
Drug Interactions
Female
Genetic Variation
Humans
Male
Middle Aged
Piperazines pharmacokinetics
Piperazines therapeutic use
Platelet Aggregation Inhibitors metabolism
Platelet Aggregation Inhibitors pharmacokinetics
Prasugrel Hydrochloride
Thiophenes pharmacokinetics
Thiophenes therapeutic use
Ticlopidine metabolism
Ticlopidine pharmacokinetics
Ticlopidine therapeutic use
Aryl Hydrocarbon Hydroxylases genetics
Aspirin therapeutic use
Coronary Disease metabolism
Piperazines metabolism
Platelet Aggregation Inhibitors therapeutic use
Thiophenes metabolism
Ticlopidine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1522-9645
- Volume :
- 30
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- European heart journal
- Publication Type :
- Academic Journal
- Accession number :
- 19429918
- Full Text :
- https://doi.org/10.1093/eurheartj/ehp157