Pharmacokinetic and pharmacodynamic evaluation of metoprolol controlled release (CR/ZOK) 50 mg in young subjects

In this steady state, cross-over study, the bioavailability and beta 1-blocking effects of metoprolol CR/ZOK 50 mg, conventional metoprolol 50 mg tablets and placebo were evaluated in 12 healthy male subjects (mean age 25 years) after once daily treatment in 5 days. The drugs were administered in a randomized order. The beta 1-blocking effect was defined as percent reduction from baseline in exercise heart rate. The plasma concentration-time profile following metoprolol CR/ZOK 50 mg administration was more even compared to conventional metoprolol tablets, with significantly lower Cmax (mean: 71 vs 221 nmol/L) and significantly higher Cmin (mean: 39 vs 6 nmol/L) for the CR/ZOK formulation. This difference in plasma concentrations was also well reflected by a significantly lower fluctuation index for metoprolol CR/ZOK 50 mg compared with the conventional 50 mg tablet (mean: 69 vs 529%). There was, however, no difference in systemic bioavailability between the two metoprolol formulations (90% confidence limits: 86-106%). The beta 1-blockade was also more even after metoprolol CR/ZOK 50 mg compared to conventional tablets with a significantly lower Emax (mean: 14 vs 19%) and higher Emin (mean: 9 vs 0%) for CR/ZOK. The total effect over a dosage interval, defined as area under the effect curve, was significantly higher for metoprolol CR/ZOK compared to conventional tablets (90% confidence limits: 123-213%). In conclusion, once daily administration of metoprolol CR/ZOK 50 mg to young healthy subjects resulted in smooth plasma concentration and produced a significant beta 1-blocking effect for 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
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