title: Nonresponders to clopidogrel: pharmacokinetics and interactions involved.
abstract: BACKGROUND
  The use of clopidogrel and aspirin has become standard therapy in patients with acute coronary syndromes and stent implantation. However, concern arises because about 25% of subjects are nonresponders to clopidogrel. This nonresponsiveness is associated with a threefold increase in adverse outcomes. Clopidogrel resistance is multifactorial, but genetic polymorphisms in clopidogrel's metabolic activation (e.g., cytochrome P450 2C19) and drug-drug interactions at this level (e.g., between proton pump inhibitors (PPIs) and clopidogrel) are both associated with decreased clopidogrel efficacy. Despite all PPIs being potent inhibitors of CYP2C19, evidence about their clinical impact is controversial.
  
  
  METHODS
  Pharmacogenomic and pharmacokinetic aspects of clopidogrel nonresponsiveness were considered in detail.
  
  
  RESULTS
  The reader will gain an exhaustive review of the current state of the controversial issues regarding genetic polymorphisms and drug-drug interactions affecting clopidogrel efficacy.
  
  
  CONCLUSIONS
  It is important to consider clopidogrel resistance in some patients and establish strategies to handle this problem (e.g., genotyping, platelet aggregability tests, new antiplatelet drugs). The combined use of PPIs and clopidogrel is at present regulated by the FDA and EMEA; however, the risk/benefit balance should be made for each patient individually.
authors.affiliation: Department of Cardiology & Cardiovascular Surgery, FLENI, Montañeses 2325 (1428), Buenos Aires, Argentina. marianoagiorgi@hotmail.com
authors.forename: Mariano A
authors.initials: MA
authors.lastname: Giorgi
authors.forename: Guillermo
authors.initials: G
authors.lastname: Di Girolamo
authors.forename: Claudio D
authors.initials: CD
authors.lastname: González
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy; D001711:Biotransformation / Q000187:drug effects / Q000235:genetics; D000077144:Clopidogrel; D004347:Drug Interactions; D004351:Drug Resistance; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D054328:Proton Pump Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine