Comparative bioavailability and effect studies on metoprolol* administered as ordinary and slow‐release tablets in single and multiple doses

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Abstract
The bioavailability, plasma levels and pharmacological effects of 100 mg of metoprolol tartrate administered as an ordinary tablet and as two different slow‐release (SR) preparations were compared in healthy volunteers after single and multiple doses in one series of experiments. In another the urinary excretion of metoprolol and total radioactivity during 72 hours were determined after single doses of 50 mg of metoprolol‐(3H) tartrate in solution and in two SR tablets with different dissolution rates. Administration of metoprolol in SR form reduced the peak plasma levels and delayed the time to reach the peak in comparison with the ordinary tablet. The areas under the plasma concentration curves (AUC) after single doses and between two doses in steady state were almost identical for the SR tablets and the ordinary one. Administration of metoprolol in SR form did not significantly influence the urinary recovery of metoprolol (about 3% of the dose) or the fraction of the radioactive dose excreted via the kidney (>97% for each preparation).The elimination half‐life determined from the post‐absorptive phase of the ordinary tablet was 4.0±0.6 hours. The effect on the exercise heart rate and the blood pressure declined at the same constant rate in the post‐absorptive phase and the rate was virtually identical for the different types of tablets. The time for 50% reduction of the maximum effect was about 8 hours. Both of the effect variables were linearly related to the log plasma concentration for the ordinary tablet and the relationships could be described by the same regression line. No significant correlation between the effects and the plasma levels was obtained for the SR tablets. Despite substantial differences between the peak plasma levels of the ordinary tablet and the SR preparations, both types of tablets induced about the same maximum effects on exercise heart rate and systolic blood pressure and only slightly higher effects were recorded at the end of the dosage interval for the SR tablets.