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Eur J Clin Pharmacol (2007) 63:5156 DOI 10.1007/s00228-006-0217-9
PHARMACOKINETICS AND DISPOSITION
Terbinafine increases the plasma concentration of paroxetine after a single oral administration of paroxetine in healthy subjects
Norio Yasui-Furukori & Manabu Saito &
Yoshimasa Inoue & Takenori Niioka & Yasushi Sato &
Shoko Tsuchimine & Sunao Kaneko
Received: 2 July 2006 / Accepted: 2 October 2006 / Published online: 24 November 2006 # Springer-Verlag 2006
Abstract Objective Paroxetine is believed to be a substrate of CYP2D6. However, no information was available indicating drug interaction between paroxetine and inhibitors of CYP2D6. The aim of this study was to examine the effects of terbinafine, a potent inhibitor of CYP2D6, on pharmacokinetics of paroxetine.Methods Two 6-day courses of either a daily 150-mg of terbinafine or a placebo, with at least a 4-week washout period, were conducted. Twelve volunteers took a single oral 20-mg dose of paroxetine on day 6 of both courses. Plasma concentrations of paroxetine were monitored up to 48 h after dosing.
Results Compared with the placebo, terbinafine treatment significantly increased the peak plasma concentration (Cmax)
of paroxetine, by 1.9-fold (6.42.4 versus 12.12.9 ng/ ml, p<0.001), and the area under the plasma concentration-time curve from zero to 48 h [AUC (048)] of paroxetine by 2.5-fold (127 67 vs 318102 ng/ml, p <0.001). Elimination half-life differed significantly (15.32.4 vs
22.78.8 h, p<0.05), although the magnitude of alteration(1.4-fold) was smaller than Cmax or AUC.
Conclusion The present study demonstrated that the metabolism of paroxetine after a single oral dose was inhibited by terbinafine, suggesting that inhibition of CYP2D6 activity may lead to a change in the pharmacokinetics of paroxetine. However, further study is required to confirm this phenomenon at steady state.
Keywords Paroxetine . Terbinafine . CYP2D6 . Interaction
Introduction
Paroxetine is one of the selective serotonin transporter inhibitors (SSRI) and is widely used in the treatment of mental disorders, including depression, panic disorders, and obsessive compulsive disorder [1, 2]. Paroxetine is almost completely absorbed following oral administration. However, the drug undergoes extensive first pass metabolism [3, 4]. As a result, less than 50% of a single dose of paroxetine reaches the general circulation. Paroxetine is eliminated by metabolism involving oxidation, demethylation, and conjugation [5].
An early in vivo study using healthy volunteers demonstrated a cosegregation between...