title: Effects of paroxetine on the pharmacokinetics and pharmacodynamics of immediate-release and extended-release metoprolol.
abstract: OBJECTIVE
  To compare the effects of paroxetine on the pharmacokinetics and pharmacodynamics of the immediate-release (IR) and extended-release (ER) formulations of metoprolol.
  
  
  METHODS
  Prospective, randomized, open-label, 3-way crossover study.
  
  
  METHODS
  General clinical research center.
  
  
  METHODS
  Fifteen healthy volunteers with at least one active cytochrome P450 (CYP) CYP2D6 allele (CYP2D6*1 or CYP2D6*2).
  
  
  METHODS
  In each of three phases conducted in random sequence, subjects received one of three metoprolol formulations administered on day 1: a single dose of metoprolol ER 100 mg, a single dose of metoprolol ER 200 mg, or two 100-mg doses of metoprolol IR administered 12 hours apart. Oral paroxetine 20 mg/day was then given alone on days 2-7 and coadministered with the same metoprolol formulation on day 8. Subjects received each of the other two formulations during the next two phases, with a 14-day washout period between each phase.
  
  
  RESULTS
  After receiving metoprolol on days 1 (before paroxetine) and 8 (after paroxetine), S- and R-metoprolol pharmacokinetic parameters and exercise heart rate and blood pressure responses were measured. The mean area under the plasma concentration-time curve values of both S- and R-metoprolol for each formulation were increased approximately 3- and 4-fold, respectively, by paroxetine. Paroxetine significantly increased the S- and R-metoprolol maximum concentration (C(max)) of each formulation and increased the elimination half-life of both isomers approximately 2-fold. When metoprolol IR was given with paroxetine, the S-metoprolol C(max) was significantly greater than that of either the 100-mg or 200-mg ER products. The maximum effect of metoprolol IR on heart rate was significantly greater than that of metoprolol ER 200 mg, independent of whether the agents were administered alone or with paroxetine. Both the heart rate and systolic blood pressure area under the effect-time curve values were significantly decreased by paroxetine.
  
  
  CONCLUSIONS
  Paroxetine significantly inhibits the metabolism of both metoprolol IR and ER, resulting in an increase in the magnitude and duration of [H9252]-blockade. The potential risk of adverse effects from excessive β-blockade may be greater with metoprolol IR than with metoprolol ER because of the significantly higher peak S-metoprolol plasma concentrations achieved with the IR formulation. Thus, if paroxetine treatment is indicated in patients receiving metoprolol, use of the ER formulation may reduce the risk of adverse effects.
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. rparker@uthsc.edu
authors.forename: Robert B
authors.initials: RB
authors.lastname: Parker
authors.forename: Judith E
authors.initials: JE
authors.lastname: Soberman
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000328:Adult; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D003692:Delayed-Action Preparations; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D017374:Paroxetine / Q000494:pharmacology*; D011446:Prospective Studies; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013237:Stereoisomerism; D055815:Young Adult
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D019389:Cytochrome P-450 CYP2D6; D003692:Delayed-Action Preparations; D008790:Metoprolol; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors