title: Genetic polymorphisms of CYP2C19 2 and ABCB1 C3435T affect the pharmacokinetic and pharmacodynamic responses to clopidogrel in 401 patients with acute coronary syndrome.
abstract: OBJECTIVE
  Clopidogrel, an inhibitor of platelet ADP P2Y12 receptors, plays an important role in the prevention of stent thrombosis. However, some patients do not attain adequate antiplatelet effects. Studies have shown that the genetic variation in CYP2C19*2 is associated with an impaired response to clopidogrel. This study was designed to investigate the genetic variants of 21 genes involving in the absorption, metabolism, and pharmacodynamics of clopidogrel. The effects of these genes on the plasma level of clopidogrel and its metabolites (active clopi-H4 and inactive CLPM) and platelet reactivity were also studied.
  
  
  RESULTS
  401 acute coronary syndrome (ACS) patients received either a 300 mg loading dose following 75 mg maintenance dose daily or a 75mg maintenance dose daily of clopidogrel. The inhibition of platelets was assessed using light transmittance aggregometry. Plasma concentrations of clopidogrel as well as its active (clopi-H4) and inactive (CLPM) metabolites were measured using HPLC-MS-MS method. Among 21 genes, the carriers of CYP2C19*2 were associated with lower exposure to its active (clopi-H4) and inactive (CLPM) metabolites (both P<0.05 vs. non-carriers) and thus decreased platelet inhibition (P<0.05 vs. non-carriers). Notably, the carriers of ABCB1 C3435T were associated with lower levels of plasma clopidogrel and its active (clopi-H4) and inactive (CLPM) metabolites (all P<0.05 vs. non-carriers) which also correlated with subsequently decreased platelet inhibition (P<0.05 vs. non-carriers). There were no obvious effects of other studied genes on clopidogrel.
  
  
  CONCLUSIONS
  CYP2C19*2 is a determinant for the formation of the active metabolite of clopidogrel and its antiplatelet effects. Meanwhile, ABCB1 C3435T plays an important role in intestinal absorption of clopidogrel which further affects the exposure to the active metabolite of clopidogrel and platelet aggregation.
authors.affiliation: Division of Cardiology, The First Affiliated Hospital, Anhui Medical University, Hefei 230032, China; Division of Cardiology, The Fourth Affiliated Hospital, Anhui Medical University, Hefei 230032, China.
authors.forename: Xia-Qin
authors.initials: XQ
authors.lastname: Wang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
authors.forename: Chen-Lin
authors.initials: CL
authors.lastname: Shen
authors.affiliation: Division of Cardiology, The First Affiliated Hospital, Anhui Medical University, Hefei 230032, China. Electronic address: wangbangning@medmail.com.cn.
authors.forename: Bang-Ning
authors.initials: BN
authors.lastname: Wang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei 230032, China. Electronic address: mathdrug@sina.com.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Huang
authors.affiliation: Division of Cardiology, The Second Affiliated Hospital, Anhui Medical University, Hefei 230032, China.
authors.forename: Zhang-le
authors.initials: ZL
authors.lastname: Hu
authors.affiliation: Institute for Liver Diseases of Anhui Medical University (AMU), Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
keywords: ACS; Clopidogrel; Genetic polymorphisms; Pharmacodynamics; Pharmacokinetics