title: Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel.
abstract: BACKGROUND
  Thienopyridines are metabolized to active metabolites that irreversibly inhibit the platelet P2Y(12) adenosine diphosphate receptor. The pharmacodynamic response to clopidogrel is more variable than the response to prasugrel, but the reasons for variation in response to clopidogrel are not well characterized.
  
  
  OBJECTIVE
  To determine the relationship between genetic variation in cytochrome P450 (CYP) isoenzymes and the pharmacokinetic/pharmacodynamic response to prasugrel and clopidogrel.
  
  
  METHODS
  Genotyping was performed for CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP3A4 and CYP3A5 on samples from healthy subjects participating in studies evaluating pharmacokinetic and pharmacodynamic responses to prasugrel (60 mg, n = 71) or clopidogrel (300 mg, n = 74).
  
  
  RESULTS
  In subjects receiving clopidogrel, the presence of the CYP2C19*2 loss of function variant was significantly associated with lower exposure to clopidogrel active metabolite, as measured by the area under the concentration curve (AUC(0-24); P = 0.004) and maximal plasma concentration (C(max); P = 0.020), lower inhibition of platelet aggregation at 4 h (P = 0.003) and poor-responder status (P = 0.030). Similarly, CYP2C9 loss of function variants were significantly associated with lower AUC(0-24) (P = 0.043), lower C(max) (P = 0.006), lower IPA (P = 0.046) and poor-responder status (P = 0.024). For prasugrel, there was no relationship observed between CYP2C19 or CYP2C9 loss of function genotypes and exposure to the active metabolite of prasugrel or pharmacodynamic response.
  
  
  CONCLUSIONS
  The common loss of function polymorphisms of CYP2C19 and CYP2C9 are associated with decreased exposure to the active metabolite of clopidogrel but not prasugrel. Decreased exposure to its active metabolite is associated with a diminished pharmacodynamic response to clopidogrel.
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. jtbrandt@lilly.com
authors: J T
authors: JT
authors: Brandt
authors: S L
authors: SL
authors: Close
authors: S J
authors: SJ
authors: Iturria
authors: C D
authors: CD
authors: Payne
authors: N A
authors: NA
authors: Farid
authors: C S
authors: CS
authors: Ernest
authors: D R
authors: DR
authors: Lachno
authors: D
authors: D
authors: Salazar
authors: K J
authors: KJ
authors: Winters
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002986:Clinical Trials as Topic; D000077144:Clopidogrel; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D000068799:Prasugrel Hydrochloride; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12; D012016:Reference Values; D012107:Research Design; D012189:Retrospective Studies; D013876:Thiophenes / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C548576:P2RY12 protein, human; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes; D000077144:Clopidogrel; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine