title: Influence of metoprolol dosage release formulation on the pharmacokinetic drug interaction with paroxetine.
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 (AUC(0-24h)) 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.
authors.affiliation: University of Michigan College of Pharmacy, 428 Church St, Ann Arbor, MI 48109-1065, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Stout
authors.forename: Jace
authors.initials: J
authors.lastname: Nielsen
authors.forename: Lynda S
authors.initials: LS
authors.lastname: Welage
authors.forename: Michael
authors.initials: M
authors.lastname: Shea
authors.forename: Robert
authors.initials: R
authors.lastname: Brook
authors.forename: Kevin
authors.initials: K
authors.lastname: Kerber
authors.forename: Barry E
authors.initials: BE
authors.lastname: Bleske
mesh_terms: D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D000328:Adult; D018592:Cross-Over Studies; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008790:Metoprolol / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D008875:Middle Aged; D017374:Paroxetine / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013237:Stereoisomerism; D055815:Young Adult
chemical_list: D000319:Adrenergic beta-Antagonists; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003692:Delayed-Action Preparations; D004791:Enzyme Inhibitors; D008790:Metoprolol; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors
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