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.

Figure I

Average plasma concentration versus time curves for total metoprolol (S + R) following 50 mg metoprolol IR. Error bars depict standard deviation. ■: Metoprolol alone, N=10; ▲:Metoprolol + paroxetine, N=10.

Figure II

Average plasma concentration versus time curves for total metoprolol (S + R) following 100 mg metoprolol ER. Error bars depict standard deviation. ■: Metoprolol alone, N=9; ▲:Metoprolol + paroxetine, N=10.

Figure III

Metoprolol IR AUC following 50 mg oral dose, with and without paroxetine. mean metoprolol AUC 223 ng*h/mL without paroxetine, 949 ng*h/mL with paroxetine.

Figure IV

Metoprolol ER AUC following 100 mg oral dose, with and without paroxetine. mean metoprolol AUC 265 ng*h/mL without paroxetine, 1121 ng*h/mL with paroxetine.

Figure V

Metoprolol IR S/R enantiomer AUC ratio following 50 mg oral dose, with and without paroxetine. mean S/R ratio 1.6 without paroxetine, 1.2 with paroxetine.

Figure VI

Metoprolol ER S/R enantiomer AUC ratio following 100 mg oral dose, with and without paroxetine. mean S/R ratio 1.7 without paroxetine, 1.2 with paroxetine.