Key result
Paroxetine treatment significantly increased the AUC of (S)-metoprolol from 279 to 1,418 ng x h/mL (P<0.001) and enhanced the metoprolol-induced decrease in exercise heart rate.
Why the study?
Does paroxetine alter the pharmacokinetics and pharmacodynamics of metoprolol in healthy male volunteers?
Does paroxetine alter the pharmacokinetics and pharmacodynamics of metoprolol in healthy male volunteers?
Absolute Event Rate: 1418% vs 279%
p-value: p=<0.001
Multiple-dose paroxetine significantly increases metoprolol exposure and beta-blockade, suggesting a dose reduction of metoprolol may be required when co-administered to prevent bradycardia.
May warrant metoprolol dose reduction with paroxetine to limit bradycardia risk; leaves open confirmation in patients.
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 1,340 ng x h/mL [P < .001] and 279 to 1,418 ng x h/mL [P < .001], respectively), with an approximately twofold increase in both maximum plasma concentration and terminal elimination half-life. Furthermore, the (S)/(R) AUC ratio was significantly decreased, from 1.72 to 1.07 (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 beta-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 beta-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.
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Hemeryck et al. (2000) studied Healthy volunteers (n=8). Paroxetine vs. Baseline (before paroxetine treatment) was evaluated on Mean area under the plasma concentration-time curve (AUC) of (S)-metoprolol (p=<0.001). Paroxetine treatment significantly increased the AUC of (S)-metoprolol from 279 to 1,418 ng x h/mL (P<0.001) and enhanced the metoprolol-induced decrease in exercise heart rate.
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