CYP2C19*17 increases clopidogrel-mediated platelet inhibition but does not alter the pharmacokinetics of the active metabolite of clopidogrel
- Authors:
-
- Pedersen, Rasmus Steen ;
- Nielsen, Flemming ;
- Stage, Tore Bjerregaard ;
-
Vinholt, Pernille Just
;
Close
0000-0002-2035-0169
Clinical Biochemistry, Department of Clinical Research, Faculty of Health Sciences, SDU - Achwah, Alaa Bilal El ;
-
Damkier, Per
;
Close0000-0003-0591-7187
Clinical Biochemistry, Department of Clinical Research, Faculty of Health Sciences, SDU - Brøsen, Kim
- DOI:
- 10.1111/1440-1681.12297
- Abstract:
- The aim of the present study was to determine the impact of CYP2C19*17 on the pharmacokinetics and pharmacodynamics of the active metabolite of clopidogrel and the pharmacokinetics of proguanil. Thus, we conducted an open-label two-phase cross-over study in 31 healthy male volunteers (11 CYP2C19*1/*1, 11 CYP2C19*1/*17 and nine CYP2C19*17/*17). In Phase A, the pharmacokinetics of the derivatized active metabolite of clopidogrel (CAMD) and platelet function were determined after administration of a single oral dose of 600 mg clopidogrel (Plavix; Sanofi-Avensis, Horsholm, Denmark). In Phase B, the pharmacokinetics of proguanil and its metabolites cycloguanil and 4-chlorphenylbiguanide (4-CPB) were determined in 29 of 31 subjects after a single oral dose of 200 mg proguanil given as the combination drug Malarone (GlaxoSmithKline Pharma, Brondby, Denmark). Significant correlations were found between the area under the time-concentration curve (AUC0-∞ ) of CAMD and both the absolute ADP-induced P2Y12 receptor-activated platelet aggregation (r = -0.60, P = 0.0007) and the percentage inhibition of aggregation (r = 0.59, P = 0.0009). In addition, the CYP2C19*17/*17 and CYP2C19*1/*17 genotype groups had significantly higher percentage inhibition of platelet aggregation compared with the CYP2C19*1/*1 subjects (geometric mean percentage inhibition of 84%, 73% and 63%, respectively; P = 0.014). Neither the absolute ADP-induced P2Y12 receptor-activated platelet aggregation, exposure to CAMD nor the pharmacokinetic parameters of proguanil, cycloguanil and 4-CPB exhibited any significant differences among the genotype groups. In conclusion, carriers of CYP2C19*17 exhibit higher percentage inhibition of platelet aggregation, but do not have significantly lower absolute P2Y12 receptor-activated platelet aggregation or higher exposure to the active metabolite after a single oral administration of 600 mg clopidogrel.
- Type:
- Journal article
- Language:
- English
- Published in:
- Clinical and Experimental Pharmacology and Physiology, 2014, Vol 41, Issue 11, p. 870-78
- Keywords:
- Area Under Curve; Cross-Over Studies; Cytochrome P-450 CYP2C19; Dose-Response Relationship, Drug; Healthy Volunteers; Humans; Male; Platelet Aggregation; Polymorphism, Single Nucleotide; Proguanil; Prospective Studies; Purinergic P2Y Receptor Antagonists; Substrate Specificity; Ticlopidine; Time Factors
- Main Research Area:
- Medical science
- Publication Status:
- Published
- Review type:
- Peer Review
- Submission year:
- 2014
- Scientific Level:
- Scientific
- ID:
- 269927916
