CYP2C19*17 increases clopidogrel‐mediated platelet inhibition but does not alter the pharmacokinetics of the active metabolite of clopidogrel1. (November 2014)

• Record Type: Journal Article
• Authors: Pedersen, Rasmus Steen; Nielsen, Flemming; Stage, Tore Bjerregaard; Vinholt, Pernille Just; el Achwah, Alaa Bilal; Damkier, Per; Brosen, Kim
• Is Part Of: Clinical and experimental pharmacology and physiology. Volume 41:Number 11(2014:Nov.)
• Page Start: 870
• Page End: 878
• Publication Date: 2014-11
• Subjects: Clinical pharmacology -- Periodicals; Pharmacology, Experimental -- Periodicals; Physiology, Experimental -- Periodicals; Physiology, Pathological -- Periodicals; 615.1
• DOI: 10.1111/1440-1681.12297
• Languages: English
• ISSNs: 0305-1870

Abstract

<abstract abstract-type="main" id="cep12297-abs-0001"> <title>Summary</title> <p>The aim of the present study was to determine the impact of <italic>CYP2C19*17</italic> 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 <italic>CYP2C19*1/*1</italic>, 11 <italic>CYP2C19*1/*17</italic> and nine <italic>CYP2C19*17/*17</italic>). 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 (AUC<sub>0–∞</sub>) of CAMD and both the absolute ADP‐induced P2Y<sub>12</sub> receptor‐activated platelet aggregation (<italic>r = </italic>−0.60, <italic>P</italic> = 0.0007) and the percentage inhibition of aggregation (<italic>r = </italic>0.59, <italic>P</italic> = 0.0009). In addition, the <italic>CYP2C19*17/*17</italic> and <italic>CYP2C19*1/*17</italic> genotype groups had significantly higher percentage inhibition of platelet aggregation compared with the <italic>CYP2C19*1/*1</italic> subjects (geometric mean percentage inhibition of 84%, 73% and 63%, respectively; <italic>P</italic> = 0.014). Neither the absolute ADP‐induced P2Y<sub>12</sub> 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 <italic>CYP2C19*17</italic> exhibit higher percentage inhibition of platelet aggregation, but do not have significantly lower absolute P2Y<sub>12</sub> receptor‐activated platelet aggregation or higher exposure to the active metabolite after a single oral administration of 600 mg clopidogrel.</p> </abstract>