Effect of Clopidogrel and Ticlopidine on Cytochrome P450 2B6 Activity as Measured by Bupropion Hydroxylation|[ast]|

doi:doi:10.1016/j.clpt.2005.02.010

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Clinical Pharmacology & Therapeutics (2005) 77, 553–559; doi: 10.1016/j.clpt.2005.02.010

Effect of Clopidogrel and Ticlopidine on Cytochrome P450 2B6 Activity as Measured by Bupropion Hydroxylation^*

Miia Turpeinen MD^1,2, Ari Tolonen PhD^1,2, Jouko Uusitalo MSc^1,2, Jorma Jalonen PhD^1,2, Olavi Pelkonen MD, PhD^1,2 and Kari Laine MD, PhD^1,2

¹Departments of Pharmacology and Toxicology and Chemistry, University of Oulu, and Novamass Analytical Ltd,Oulu
²Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku.

Correspondence: Miia Turpeinen, MD, Department of Pharmacology and Toxicology, PO Box 5000, 90014 University of Oulu, Oulu, Finland. E-mail: miia.turpeinen@oulu.fi

^*This work was funded by grants from the Finnish Technological Research Agency (Pelkonen) and Turku University Hospital Grant EVO13390 (Laine) and supported by grants from the Finnish Cultural Foundation, Finnish Medical Society Duodecim, Farmos Research and Science Foundation, and Juliana von Wendt Foundation (Turpeinen).

Received 8 December 2004; Accepted 25 February 2005.

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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.