Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation.
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.
Turpeinen
Miia
M
Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland. miia.turpeinen@oulu.fi
Tolonen
Ari
A
Uusitalo
Jouko
J
Jalonen
Jorma
J
Pelkonen
Olavi
O
Laine
Kari
K
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*
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