title: Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction.
abstract: BACKGROUND
  We observed that the prodrug clopidogrel was less effective in inhibiting platelet aggregation with coadministration of atorvastatin during point-of-care platelet function testing. Because atorvastatin is metabolized by cytochrome P450 (CYP) 3A4, we hypothesized that clopidogrel might be activated by CYP3A4.
  
  
  RESULTS
  Platelet aggregation was measured in 44 patients undergoing coronary artery stent implantation treated with clopidogrel or clopidogrel plus pravastatin or atorvastatin, and in 27 volunteers treated with clopidogrel and either erythromycin or troleandomycin, CYP3A4 inhibitors, or rifampin, a CYP3A4 inducer. Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of clopidogrel in a dose-dependent manner. Percent platelet aggregation was 34+/-23, 58+/-15 (P=0.027), 74+/-10 (P=0.002), and 89+/-7 (P=0.001) in the presence of clopidogrel and 0, 10, 20, and 40 mg of atorvastatin, respectively. Erythromycin attenuated platelet aggregation inhibition (55+/-12 versus 42+/-12% platelet aggregation; P=0.002), as did troleandomycin (78+/-18 versus 45+/-18% platelet aggregation; P<0.0003), whereas rifampin enhanced platelet aggregation inhibition (33+/-18 versus 56+/-20% platelet aggregation, P=0.001).
  
  
  CONCLUSIONS
  CYP3A4 activates clopidogrel. Atorvastatin, another CYP3A4 substrate, competitively inhibits this activation. Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel.
authors.affiliation: Department of Anesthesiology, University of Michigan, Ann Arbor, USA. weiclau@umich.edu
authors.forename: Wei C
authors.initials: WC
authors.lastname: Lau
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Waskell
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
authors.forename: Charlene J
authors.initials: CJ
authors.lastname: Neer
authors.forename: Kevin
authors.initials: K
authors.lastname: Horowitz
authors.forename: Amy S
authors.initials: AS
authors.lastname: Hopp
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tait
authors.forename: David G M
authors.initials: DG
authors.lastname: Carville
authors.forename: Kirk E
authors.initials: KE
authors.lastname: Guyer
authors.forename: Eric R
authors.initials: ER
authors.lastname: Bates
mesh_terms: D000293:Adolescent; D000328:Adult; D000069059:Atorvastatin; D001944:Breath Tests; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004917:Erythromycin / Q000494:pharmacology; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D017035:Pravastatin / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011758:Pyrroles; D004917:Erythromycin; D000069059:Atorvastatin; D000077144:Clopidogrel; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017035:Pravastatin; D013988:Ticlopidine