Inhibition of metoprolol metabolism and potentiation of its effects by paroxetine in routinely treated patients with acute myocardial infarction (AMI).
OBJECTIVE
To investigate the influence of paroxetine on metoprolol concentrations and its effect in patients treated for acute myocardial infarction (AMI) who are routinely given paroxetine as a co-treatment of depression.


METHODS
We recruited 17 depressed AMI patients who received metoprolol as a routine part of their therapy (mean dose 75 +/- 39 mg/day). Patients were genotyped for CYP2D6 3, 4 and gene duplication. Metoprolol and alpha-hydroxy-metoprolol were analyzed in plasma 0, 2, 6 and 12 h post-dose. Heart rates (HR) at rest were registered after each sampling. Paroxetine 20 mg daily was then administered, and all measurements were repeated on day 8.


RESULTS
All patients were genotypically extensive metabolizers (EMs) (nine with 1/1 and eight with 1/3 or 4). Following the administration of paroxetine, mean metoprolol areas under the concentration-time curve (AUC) increased (1064 +/- 1213 to 4476 +/- 2821 nM x h/mg per kg, P = 0.0001), while metabolite AUCs decreased (1492 +/- 872 to 348 +/- 279 n M x h/mg per kg, P < 0.0001), with an increase of metabolic ratios (MR) (0.9 +/- 1.3 to 26 +/- 29; P < 0.0001). Mean HRs were significantly lower after the study week at each time point. Mean area under the HR versus time curve (AUEC) decreased (835 +/- 88 to 728 +/- 84 beats x h/min; P = 0.0007). Metoprolol AUCs correlated with patients' AUECs at the baseline (Spearman r = -0.64, P < 0.01), but not on the eighth day of the study. A reduction of metoprolol dose was required in two patients due to excessive bradycardia and severe orthostatic hypotension. No other adverse effects of the drugs were identified.


CONCLUSIONS
A pronounced inhibition of metoprolol metabolism by paroxetine was observed in AMI patients, but without serious adverse effects. We suggest, however, that the metoprolol dose is controlled upon initiation and withdrawal of paroxetine.
Course of Clinical Pharmacology, Department of Hospital Therapy, St. Petersburg I.I. Mechnikov State Medical Academy, Piskarevsky Prospect, 47, 195 067 St Petersburg, Russia. ksenia_goryachkina@yahoo.com
Ksenia
K
Goryachkina
Aleksandra
A
Burbello
Svetlana
S
Boldueva
Svetlana
S
Babak
Ulf
U
Bergman
Leif
L
Bertilsson
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000368:Aged; D000369:Aged, 80 and over; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D001919:Bradycardia / Q000139:chemically induced; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D003863:Depression / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007024:Hypotension, Orthostatic / Q000139:chemically induced; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy*; D017374:Paroxetine / Q000494:pharmacology* / Q000627:therapeutic use
D000319:Adrenergic beta-Antagonists; D018687:Antidepressive Agents, Second-Generation; D017374:Paroxetine; C029504:alpha-hydroxymetoprolol; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol