The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance

• Published in: Clinical pharmacology and therapeutics Vol. 84; no. 2; p. 236
• Main Authors: Kim, K A, Park, P W, Hong, S J, Park, J-Y
• Format: Journal Article
• Language: English
• Published: United States 01.08.2008
• Subjects: Adult; Area Under Curve; Aryl Hydrocarbon Hydroxylases - genetics; Blood Platelets - drug effects; Cytochrome P-450 CYP2C19; Drug Administration Schedule; Drug Resistance - genetics; Female; Genotype; Humans; Korea; Male; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - blood; Platelet Aggregation Inhibitors - pharmacokinetics; Platelet Aggregation Inhibitors - pharmacology; Polymorphism, Genetic; Ticlopidine - administration & dosage; Ticlopidine - analogs & derivatives; Ticlopidine - blood; Ticlopidine - pharmacokinetics; Ticlopidine - pharmacology
• ISSN: 1532-6535
• DOI: 10.1038/clpt.2008.20

We evaluated the effect of the CYP2C19 genotype on the pharmacokinetics and pharmacodynamcis of clopidogrel. Twenty-four subjects were divided into three groups on the basis of their CYP2C19 genotype: homozygous extensive metabolizers (homoEMs, n = 8), heterozygous EMs (heteroEMs, n = 8), and poor metabolizers (PMs, n = 8). After a single 300-mg loading dose of clopidogrel on day 1, followed by a 75-mg daily maintenance dose from days 2 to 7, we measured the plasma levels of clopidogrel and assessed the antiplatelet effect as pharmacodynamics. The mean clopidogrel area under the curve (AUC) for PMs was 1.8- and 2.9-fold higher than that for heteroEMs and homoEMs, respectively (P = 0.013). The mean peak plasma concentration in PMs was 1.8- and 4.7-fold higher than that of heteroEMs and homoEMs, respectively (P = 0.008). PMs exhibited a significantly lower antiplatelet effect than heteroEMs or homoEMs (P < 0.001). From these findings it is clear that the CYP2C19 genotype affects the plasma levels of clopidogrel and modulates the antiplatelet effect of clopidogrel.