Influencia Del Metoprolol Con Respecto A La Interacion Con Paroxetina

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J Clin Pharmacol. Author manuscript; available in PMC 2011 March 1.
Published in final edited form as: J Clin Pharmacol. 2011 March ; 51(3): 389–396. doi:10.1177/0091270010365559.

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The influence of metoprolol dosage release formulation on the pharmacokinetic drug interaction withparoxetine
Stephen M. Stout, Pharm.D., M.S., BCPS1,a, Jace Nielsen, Pharm.D.1,b, Lynda S. Welage, Pharm.D., FCCP1,2, Michael Shea, M.D.3, Robert Brook, M.D.3, Kevin Kerber, M.D.4, and Barry E. Bleske, Pharm.D., FCCP1,2,* 1The University of Michigan College of Pharmacy, Ann Arbor, MI
2The

Department of Pharmacy Services, University of Michigan Health System, Ann Arbor, MI

3Department

ofInternal Medicine Division of Cardiology, Medical School, University of Michigan, Ann Arbor, MI
4Department

of Psychiatry, Medical School, University of Michigan, Ann Arbor, MI

Abstract
Studies have demonstrated an influence of dosage release formulations on drug interactions and enantiomeric plasma concentrations. Metoprolol is a commonly used β-adrenergic antagonist metabolized byCYP2D6. 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 subjects 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 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 apharmacokinetic 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 β-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.

KeywordsMetoprolol; paroxetine; pharmacokinetics; cytochrome P-450 CYP2D6; drug interactions

*

Corresponding Author Barry E. Bleske, Pharm.D., FCCP, University of Michigan College of Pharmacy, 428 Church St, Ann Arbor, MI 48109-1065. Phone: 734-764-5341, Fax: 734-763-4480, bbleske@umich.edu. aPresently employed at Lexi-Comp, Inc, Hudson, OH bPresently employed at Ann Arbor Pharmacometrics Group, AnnArbor, MI Financial Interest Disclosure: The content is solely the responsibility of the authors and does not necessarily represent the official views of NCRR or the National Institutes of Health. BB, LW: consultant and speaker’s bureau, AstraZeneca.

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BACKGROUND
Metoprolol is a selective beta adrenergic antagonist commonly used in the management of acute myocardialinfarction (MI), angina, hypertension, and cardiac arrhythmias. Metoprolol is supplied as a racemic mixture of S and R enantiomers. The S enantiomer is primarily responsible for β-receptor antagonism and is β-1 selective, whereas the R enantiomer has lower affinity and selectivity.1, 2 Metoprolol is primarily metabolized by the liver, with an estimated 65% of a dose O-demethylated, 10%α-hydroxylated, and 10% N-dealkylated.3 Cytochrome P-450 2D6 (CYP2D6) is responsible for α –hydroxylation and some Odemethylation of metoprolol with stereospecificity favoring metabolism of the R enantiomer.4 Alternate metabolic pathways are high affinity, low capacity, and readily saturable, and favor metabolism of the S enantiomer.4 Individuals exhibiting the CYP2D6 extensive metabolizer (EM) phenotype...