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

• Published in: International journal of pharmaceutics 2000-07, Vol.202 (1), p.97-102
• Main Authors: Mostafavi, S.Abolfazl, Foster, Robert T.
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Antagonists - administration & dosage; Adrenergic beta-Antagonists - blood; Adrenergic beta-Antagonists - chemistry; Animals; Antihypertensive agents; Area Under Curve; Biological and medical sciences; Cardiovascular system; Enantiomers; Male; Medical sciences; Metoprolol; Metoprolol - administration & dosage; Metoprolol - blood; Metoprolol - chemistry; Multiple dose; Pharmacokinetics; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Single dose; Stereoisomerism
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/S0378-5173(00)00430-0

The chiral β-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.