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.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Alberta, Edmonton, Canada T6G 2N8.
S A
SA
Mostafavi
R T
RT
Foster
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D000818:Animals; D019540:Area Under Curve; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D008790:Metoprolol