The influence of genetic polymorphism of Cyp2c19 isoenzyme on the pharmacokinetics of clopidogrel and its metabolites in patients with cardiovascular diseases.
An extensive investigation on pharmacokinetics of clopidogrel and its metabolites as well as pharmacodynamics of the drug was performed in patients with cardiovascular disease carrying various alleles coding CYP2C19 isoenzyme. The influence of non-genetic factors on the clopidogrel response was also studied. Plasma concentrations of clopidogrel, its carboxylic metabolite, and diastereoisomers of a thiol metabolite (the inactive H3 and the active H4) following an administration of 75 mg of the drug were determined in three groups of patients divided with respect to their CYP2C19 genotype: ultrametabolizers, extensive metabolizers, and intermediate metabolizers. The mean peak plasma concentration of H4 in intermediate metabolizers was 3.1- and 2.8-fold lower than that of ultrametabolizers (P = 0.055) and extensive metabolizers (P = 0.026), respectively. The mean H4 area under the curve (AUC0-24 h ) for intermediate metabolizers were significantly lower than that for ultrametabolizers (P = 0.046). Intermediate metabolizers exhibited a significantly higher platelet aggregation than ultrametabolizers and extensive metabolizers (P = 0.035). A multivariate analysis showed that the effect of CYP2C19*2 allele on an ADP-induced platelet aggregation was better pronounced in the presence of non-genetic risk factors (P = 0.008). We concluded that the CYP2C19*2 genotype is the primary determinant of the antiplatelet response to clopidogrel therapy.
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, Poznań, Poland.
Marta
M
Karaźniewicz-Łada
Dorota
D
Danielak
Błażej
B
Rubiś
Paweł
P
Burchardt
Grzegorz
G
Oszkinis
Franciszek
F
Główka
D019540:Area Under Curve; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
D007527:Isoenzymes; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
active H4 isomer; aggregation; clopidogrel metabolites; pharmacogenetics; platelet