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 β-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 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 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 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.

Interaksjoner mellom metoprolol og antidepressive legemidler

“…Totalt ble åtte studier/rapporter som belyser interaksjonsrisiko mellom metoprolol og antidepressiver identifisert (4)(5)(6)(7)(8)(9)(10)(11). Tabell 1 oppsummerer hovedfunn fra disse publikasjonene.…”

“…Blant annet ble treningsindusert pulsøkning redusert med 30-40 % i kombinasjon med paroksetin (4). Interaksjonen mellom metoprolol og paroksetin er senere blitt bekreftet i en studie på hjertepasienter, der plasmakonsentrasjonen av metoprolol økte drøyt fire ganger (5 (6). Denne studien viste at økningen i plasmakonsentrasjonen av metoprolol var noe mindre ved bruk av depotformulering sammenliknet med vanlig tablettformulering, men økningen var også kraftig med depotformuleringen -i stør-relsesorden 3-4 ganger (6).…”

Evaluating the Clinical Impact of Formulation Variability: A Metoprolol Extended‐Release Case Study

“…We developed a population pharmacokinetic/pharmacodynamic model in NONMEM (version 7.3) based on literature data () to determine the impact of formulation variability on EIHR. Model selection was based on physiological meaningfulness of parameter estimates, a decrease in more than 3.84 (based on) in objective function value for nested models, goodness‐of‐fit plots, prediction‐corrected visual prediction check (500 simulations), and nonparametric bootstrap (500 simulations) analyses .…”

Drug interactions of antihypertensive agents

“…Metoprolol is metabolised by the hepatic CYP2D6 system, that is inhibited by paroxetine, a widely used antidepressant and selective serotonin reuptake inhibitor. 2 The hepatic system is also inhibited by propoxyphene, an opioid pain-relief agent, available in South Africa as Distalgesic ® , although it was recently withdrawn in the USA. 3 Carvedilol is metabolised by the same system, with the same possible interactions.…”