Impact of common ABCB1 polymorphism on pharmacokinetics and pharmacodynamics of clopidogrel and its metabolites

J Clin Pharm Ther. 2015 Apr;40(2):226-31. doi: 10.1111/jcpt.12236. Epub 2014 Nov 28.


What is known and 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.

Results and discussion: 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.

What is new and conclusion: 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.

Keywords: P-glycoprotein; clopidogrel; pharmacogenetics; pharmacokinetics; platelet aggregation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Area Under Curve
  • Clopidogrel
  • Female
  • Genotype
  • Half-Life
  • Humans
  • Male
  • Metabolic Clearance Rate
  • Percutaneous Coronary Intervention / methods
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation Inhibitors / pharmacokinetics
  • Platelet Aggregation Inhibitors / pharmacology*
  • Polymorphism, Genetic
  • Polymorphism, Single Nucleotide
  • Tandem Mass Spectrometry
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / pharmacokinetics
  • Ticlopidine / pharmacology


  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Platelet Aggregation Inhibitors
  • Clopidogrel
  • Ticlopidine