Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers

Clin Pharmacol Ther. 2000 Mar;67(3):283-91. doi: 10.1067/mcp.2000.104788.

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 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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / blood
  • Adrenergic beta-Antagonists / pharmacokinetics
  • Adrenergic beta-Antagonists / pharmacology*
  • Adult
  • Anti-Arrhythmia Agents / pharmacology
  • Antidepressive Agents, Second-Generation / pharmacology
  • Antihypertensive Agents / pharmacology
  • Area Under Curve
  • Chromatography, High Pressure Liquid
  • Drug Administration Schedule
  • Half-Life
  • Humans
  • Male
  • Metoprolol / blood
  • Metoprolol / pharmacokinetics
  • Metoprolol / pharmacology*
  • Paroxetine / administration & dosage
  • Paroxetine / pharmacology*
  • Reference Values
  • Serotonin Uptake Inhibitors / pharmacology

Substances

  • Adrenergic beta-Antagonists
  • Anti-Arrhythmia Agents
  • Antidepressive Agents, Second-Generation
  • Antihypertensive Agents
  • Serotonin Uptake Inhibitors
  • Paroxetine
  • Metoprolol