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Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers
Author(s) -
Hemeryck Alex,
Lefebvre Romain A.,
De Vriendt Cindy,
Belpaire Frans M.
Publication year - 2000
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2000.104788
Subject(s) - metoprolol , pharmacokinetics , pharmacodynamics , heart rate , chronotropic , medicine , paroxetine , pharmacology , blood pressure , anesthesia , receptor , serotonin
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] and 279 to 1418 ng · 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 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. (Clin Pharmacol Ther 2000;67:283–91.) Clinical Pharmacology & Therapeutics (2000) 67 , 283–291; doi: 10.1067/mcp.2000.104788