title: CYP2C19*17 increases clopidogrel-mediated platelet inhibition but does not alter the pharmacokinetics of the active metabolite of clopidogrel.
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.
authors.affiliation: Institute of Public Health, Clinical Pharmacology, University of Southern Denmark, Odense, Denmark.
authors.forename: Rasmus Steen
authors.initials: RS
authors.lastname: Pedersen
authors.forename: Flemming
authors.initials: F
authors.lastname: Nielsen
authors.forename: Tore Bjerregaard
authors.initials: TB
authors.lastname: Stage
authors.forename: Pernille Just
authors.initials: PJ
authors.lastname: Vinholt
authors.forename: Alaa Bilal
authors.initials: AB
authors.lastname: el Achwah
authors.forename: Per
authors.initials: P
authors.lastname: Damkier
authors.forename: Kim
authors.initials: K
authors.lastname: Brosen
mesh_terms: D019540:Area Under Curve; D000077144:Clopidogrel; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D002727:Proguanil / Q000493:pharmacokinetics*; D011446:Prospective Studies; D058921:Purinergic P2Y Receptor Antagonists / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D013379:Substrate Specificity; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors
chemical_list: D058921:Purinergic P2Y Receptor Antagonists; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine; D002727:Proguanil
keywords: CYP2C19*17; clopidogrel; proguanil