title: Impact of common ABCB1 polymorphism on pharmacokinetics and pharmacodynamics of clopidogrel and its metabolites.
abstract: OBJECTIVE
  The reasons of clopidogrel (CLP) resistance are still unclear. The response to CLP may be influenced by both genetic and non-genetic factors. Among genetic factors, common polymorphisms in the gene coding glycoprotein-P (P-gp, MDR1 and ABCB1) are considered as potential determinants of the efficacy of CLP treatment. The aim of this study was to evaluate the influence of ABCB1 3435C>T genetic polymorphism on the pharmacokinetics and pharmacodynamics of CLP and its metabolites: diastereoisomers of thiol metabolite (the inactive H3 and the active H4) and inactive carboxylic derivative.
  
  
  METHODS
  The study group included 42 patients undergoing elective coronary angiography and percutaneous coronary intervention. The plasma concentrations of CLP and its metabolites were measured by a validated HPLC-MS/MS method. Whole-blood aggregation was determined with Multiplate analyzer. For evaluation of ABCB1 3435C>T polymorphism, PCR-RFLP method was applied.
  
  
  CONCLUSIONS
  It was found that Exposition to the unchanged CLP, measured by AUC0-t of the drug, was significantly lower (P = 0·012) in TT homozygotes comparing to that observed in CC and CT genotypes, although no correlation was found between platelet aggregation and ABCB1 genetic polymorphism.
  
  
  CONCLUSIONS
  Our findings show that the presence of 3435C>T allele has an impact on CLP pharmacokinetics but not on the drug pharmacodynamics. Therefore, the 3435C>T genotype may not be the primary determinant influencing the pharmacokinetics of the active H4 metabolite and antiplatelet effect of the drug.
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Karaźniewicz-Łada
authors.forename: D
authors.initials: D
authors.lastname: Danielak
authors.forename: B
authors.initials: B
authors.lastname: Rubiś
authors.forename: P
authors.initials: P
authors.lastname: Burchardt
authors.forename: A
authors.initials: A
authors.lastname: Komosa
authors.forename: M
authors.initials: M
authors.lastname: Lesiak
authors.forename: F
authors.initials: F
authors.lastname: Główka
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D019540:Area Under Curve; D000077144:Clopidogrel; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D062645:Percutaneous Coronary Intervention / Q000379:methods; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D053719:Tandem Mass Spectrometry; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: P-glycoprotein; clopidogrel; pharmacogenetics; pharmacokinetics; platelet aggregation