title: Impact of CYP3A4*1G Allele on Clinical Pharmacokinetics and Pharmacodynamics of Clopidogrel.
abstract: OBJECTIVE
  Resistance to the antiplatelet treatment with clopidogrel has both genetic and non-genetic causes. Polymorphic variants of cytochrome P450 3A4 isoenzyme involved in the bioactivation of clopidogrel might have an influence on responsiveness to the drug. The aim of this study was to evaluate the influence of CYP3A4*1G (IVS10+12G>A, rs2242480) on the pharmacokinetics and pharmacodynamics of clopidogrel.
  
  
  METHODS
  CYP3A4*1G polymorphism was determined in a group of 82 patients undergoing percutaneous coronary intervention and taking 75 mg of clopidogrel daily. Concentrations of clopidogrel and its metabolites, inactive carboxylic acid derivative and two diastereoisomers of active thiol metabolite: H3 and H4, were determined by a validated HPLC-MS/MS method. Pharmacodynamic effect was measured by an impedance method with a Multiplate analyzer. Moreover, an effect of factors, such as CYP2C19 phenotype, age, gender, body mass index and interactions with drugs metabolized by CYP3A4 were also investigated.
  
  
  RESULTS
  In the studied group allele frequencies were: wt-0.921, *1G-0.079. Pharmacokinetic parameters of clopidogrel and its metabolites were not significantly different in carriers of *1G allele, comparing to wt/wt homozygotes. Platelet aggregation was higher in heterozygotes than in wt/wt carriers; however, the difference was not statistically significant (p = 0.484). In a multivariate analysis, which included age, body mass index, co-morbidities and coadministered drugs, CYP3A4*1G was not a predictor of values of H3 and H4 pharmacokinetic parameters and platelet aggregation.
  
  
  CONCLUSIONS
  CYP3A4*1G might not be a significant contributor to the variability in pharmacokinetic and pharmacodynamic response to clopidogrel therapy.
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Święcickiego 6 St, 61-781, Poznan, Poland. danielak@ump.edu.pl.
authors.forename: Dorota
authors.identifier: http://orcid.org/0000-0001-5807-1109
authors.initials: D
authors.lastname: Danielak
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Święcickiego 6 St, 61-781, Poznan, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Karaźniewicz-Łada
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Święcickiego 6 St, 61-781, Poznan, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Wiśniewska
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Święcickiego 6 St, 61-781, Poznan, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Bergus
authors.affiliation: Department of Biology and Environmental Sciences, Poznan University of Medical Sciences, Poznan, Poland.|Department of Cardiology, J. Strus Hospital, Poznan, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Burchardt
authors.affiliation: First Department of Cardiology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Komosa
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Święcickiego 6 St, 61-781, Poznan, Poland.
authors.forename: Franciszek
authors.initials: F
authors.lastname: Główka
mesh_terms: D000368:Aged; D000483:Alleles; D015992:Body Mass Index; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004347:Drug Interactions; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; 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
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013988:Ticlopidine