Influence of metoprolol dosage release formulation on the pharmacokinetic drug interaction with paroxetine

Stephen M. Stout, Jace Nielsen, Lynda S. Welage, Michael Shea, Robert Brook, Kevin Kerber, Barry E. Bleske

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Studies have demonstrated an influence of dosage release formulations on drug interactions and enantiomeric plasma concentrations. Metoprolol is a commonly used beta-adrenergic antagonist metabolized by CYP2D6. The CYP2D6 inhibitor paroxetine has previously been shown to interact with metoprolol tartrate. This open-label, randomized, 4-phase crossover study assessed the potential differential effects of paroxetine on stereoselective pharmacokinetics of immediate-release (IR) tartrate and extended-release (ER) succinate metoprolol formulations. Ten healthy participants received metoprolol IR (50 mg) and ER (100 mg) with and without paroxetine coadministration. Blood samples were collected over 24 hours for determination of metoprolol plasma enantiomer concentrations. Paroxetine coadministration significantly increased S and R metoprolol area under the plasma concentration-time curve from time 0 to the 24-hour blood draw (AUC0-24h) by 4- and 5-fold, respectively for IR, and 3- and 4-fold, respectively, for ER. S/R AUC ratios significantly decreased. These results demonstrate a pharmacokinetic interaction between paroxetine and both formulations of metoprolol. The interaction is greater with R metoprolol, and stereoselective metabolism is lost. This could theoretically result in greater beta-blockade and lost cardioselectivity. The magnitude of the interaction was similar between metoprolol formulations, which may be attributable to low doses/drug input rates employed.

Original languageEnglish (US)
Pages (from-to)389-396
Number of pages8
JournalJournal of Clinical Pharmacology
Volume51
Issue number3
DOIs
StatePublished - Mar 2011

Bibliographical note

Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.

Keywords

  • CYP2D6
  • Metoprolol
  • cytochrome P-450
  • drug interactions
  • paroxetine
  • pharmacokinetics

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