Pharmacokinetics of metoprolol enantiomers following single and multiple administration of racemate in rat.

The chiral beta-adrenergic blocking agent metoprolol (MET), which is marketed as a racemate, is a highly extracted drug with rapid absorption. The enantiomeric disposition of MET is reported following racemic administration as a single and as multiple oral dosing four times per day for four days in male Sprague-Dawley rats (n=6 in each group). Plasma was collected and enantiomeric concentrations of MET were determined using a stereospecific HPLC assay. The R/S ratio for AUC is not statistically different from unity either after single or after multiple administration of racemate. The oral clearance after single dose was 1.99+/-0.87 and 2. 26+/-0.85 ml min(-1) kg(-1) for R- and S-MET, respectively. These values were decreased to 0.59+/-0.21 and 0.64+/-0.26 ml min(-1) kg(-1) after multiple administration of racemate. The corresponding values for the elimination half-lives were approximately 35 and 33 min after single and multiple dose administration for both enantiomers, respectively. These results may suggest a saturable first pass metabolism of MET as its enantiomers are accumulated in plasma following multiple dosing in the rat model.