Stable isotope methodology for studying the performance of metoprolol Oros tablets in comparison to conventional and slow release formulations.

Metoprolol Oros tablets were designed to deliver their drug content as a constant rate over a period of time longer than that currently recorded with slow-release dosage forms. The bioavailability of 7/95, 14/190 and 21/285 Oros tablets was compared to that of either 100 mg conventional or 200 mg slow-release Lopresor tablets in 3 two-period change over experiments. In each experiment, 6 healthy volunteers received intravenous deuterated metoprolol concomitantly with one of the Oros systems or with one of the other two formulations. The Oros tablets gave rise to lower and steady plasma levels of metoprolol over 24 h than the other formulations. Their mean absorption time was around 3 times longer than that of the slow-release tablets. The amount of the drug absorbed unchanged was linearly related to the dose. The influence of the gastrointestinal transit time on the performance of Oros tablet was limited. These studies demonstrated the value of the stable isotope methodology in bioavailability assessment for drugs presenting a high inter-subject variability in their plasma clearance such as metoprolol.