Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers

Abstract

Objective: To investigate the effect of multiple-dose paroxetine intake on the stereoselective pharmacokinetics and the pharmacodynamics of metoprolol. Methods: We conducted an open trial with two sessions in eight healthy male volunteers. Racemic metoprolol (100 mg single oral dose) was administered before and after paroxetine treatment (20 mg/day for 6 days). The (R) and (S)-metoprolol pharmacokinetics, metoprolol metabolic ratio (MR), exercise heart rate and blood pressure were assessed for 12 (pharmacodynamic data) to 24 (pharmacokinetic data) hours after each metoprolol intake. Results: Paroxetine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC) of (R)- and (S)- metoprolol significantly (169 to 1340 ng · h/mL [P < .001). The mean metoprolol MR was significantly increased, from 0.17 to 5.69 (P < .05). The AUC of the metoprolol-induced decrease in exercise heart rate versus time curve was increased, with 46% (P < .01) after multiple-dose paroxetine intake, reaching significance from 6 hours after metoprolol intake, illustrating a more sustained β-blockade. Similar results were obtained for the effect on exercise systolic blood pressure. Multiple- dose metoprolol administration combined with paroxetine can lead to an accumulation of the β-blocking (S)-enantiomer of metoprolol, possibly resulting in unacceptable bradycardia, loss of cardioselectivity, or both. Conclusion: Multiple-dose paroxetine intake affects both metoprolol pharmacokinetics and pharmacodynamics and suggests that when paroxetine is added to an ongoing metoprolol therapy, caution is warranted and a reduction of the metoprolol dose may be required to prevent undesired adverse effects.