title: Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation.
abstract: OBJECTIVE
  Our objective was to study the effect of the antiplatelet agents clopidogrel and ticlopidine on bupropion (INN, amfebutamone) hydroxylation, a probe reaction for cytochrome P450 (CYP) 2B6 activity.
  
  
  METHODS
  Twelve healthy male volunteers took a single 150-mg oral dose of bupropion either alone or after pretreatment with 75 mg clopidogrel once daily or 250 mg ticlopidine twice daily for 4 days. On day 4, a single 150-mg oral dose of bupropion was administered. Plasma concentrations of bupropion and its CYP2B6-catalyzed metabolite, hydroxybupropion, were measured for up to 72 hours.
  
  
  RESULTS
  The mean area under the plasma concentration-time curve (AUC) of hydroxybupropion calculated from time 0 to infinity was reduced by 52% ( P = .001; 95% confidence interval [CI], 39% to 66%) by clopidogrel and by 84% ( P < .0001; 95% CI, 73% to 94%) by ticlopidine. Clopidogrel reduced the AUC ratio of hydroxybupropion over bupropion by 68% ( P = .002; 95% CI, 58% to 77%) and ticlopidine by 90% ( P = .001; 95% CI, 85% to 96%). The AUC of bupropion was increased by 60% ( P = .02; 95% CI, 21% to 98%) and by 85% ( P < .0001; 95% CI, 48% to 85%) with clopidogrel and ticlopidine, respectively.
  
  
  CONCLUSIONS
  Both clopidogrel and ticlopidine significantly inhibited the CYP2B6-catalyzed bupropion hydroxylation. Patients receiving either clopidogrel or ticlopidine are likely to require dose adjustments when treated with drugs primarily metabolized by CYP2B6.
authors.affiliation: Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland. miia.turpeinen@oulu.fi
authors.forename: Miia
authors.initials: M
authors.lastname: Turpeinen
authors.forename: Ari
authors.initials: A
authors.lastname: Tolonen
authors.forename: Jouko
authors.initials: J
authors.lastname: Uusitalo
authors.forename: Jorma
authors.initials: J
authors.lastname: Jalonen
authors.forename: Olavi
authors.initials: O
authors.lastname: Pelkonen
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D016642:Bupropion / Q000493:pharmacokinetics*; D000077144:Clopidogrel; D018592:Cross-Over Studies; D065702:Cytochrome P-450 CYP2B6; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006900:Hydroxylation; D008297:Male; D010089:Oxidoreductases, N-Demethylating; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
chemical_list: D018765:Dopamine Uptake Inhibitors; D010975:Platelet Aggregation Inhibitors; D016642:Bupropion; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D013988:Ticlopidine