Effects of Paroxetine on the Pharmacokinetics and Pharmacodynamics of Immediate‐Release and Extended‐Release Metoprolol

Abstract

To compare the effects of paroxetine on the pharmacokinetics and pharmacodynamics of the immediate-release (IR) and extended-release (ER) formulations of metoprolol. Prospective, randomized, open-label, 3-way crossover study. General clinical research center. Fifteen healthy volunteers with at least one active cytochrome P450 (CYP) CYP2D6 allele (CYP2D6*1 or CYP2D6*2). In each of three phases conducted in random sequence, subjects received one of three metoprolol formulations administered on day 1: a single dose of metoprolol ER 100 mg, a single dose of metoprolol ER 200 mg, or two 100-mg doses of metoprolol IR administered 12 hours apart. Oral paroxetine 20 mg/day was then given alone on days 2-7 and coadministered with the same metoprolol formulation on day 8. Subjects received each of the other two formulations during the next two phases, with a 14-day washout period between each phase. After receiving metoprolol on days 1 (before paroxetine) and 8 (after paroxetine), S- and R-metoprolol pharmacokinetic parameters and exercise heart rate and blood pressure responses were measured. The mean area under the plasma concentration-time curve values of both S- and R-metoprolol for each formulation were increased approximately 3- and 4-fold, respectively, by paroxetine. Paroxetine significantly increased the S- and R-metoprolol maximum concentration (C(max)) of each formulation and increased the elimination half-life of both isomers approximately 2-fold. When metoprolol IR was given with paroxetine, the S-metoprolol C(max) was significantly greater than that of either the 100-mg or 200-mg ER products. The maximum effect of metoprolol IR on heart rate was significantly greater than that of metoprolol ER 200 mg, independent of whether the agents were administered alone or with paroxetine. Both the heart rate and systolic blood pressure area under the effect-time curve values were significantly decreased by paroxetine. Paroxetine significantly inhibits the metabolism of both metoprolol IR and ER, resulting in an increase in the magnitude and duration of [H9252]-blockade. The potential risk of adverse effects from excessive β-blockade may be greater with metoprolol IR than with metoprolol ER because of the significantly higher peak S-metoprolol plasma concentrations achieved with the IR formulation. Thus, if paroxetine treatment is indicated in patients receiving metoprolol, use of the ER formulation may reduce the risk of adverse effects.