ENANTIOSELECTIVE AND DIASTEREOSELECTIVE ASPECTS OF THE OXIDATIVE-METABOLISM OF METOPROLOL

Enantio- and diastereoselective aspects of oxidative metabolism of metoprolol (1) were examined in the presence of rat liver and human liver microsomes using a pseudoracemate of 1, made up of equal molar (2R)-1-d0 and (2S)-1-d2, as substrate. Both O-demethylation and α-hydroxylation showed only slight enantioselectivity, 2R 2S ratios being 1.18 and 0.93 for these pathways in rat liver microsomes and 1.09 and 0.92 in human liver microsomes. In the presence of the rat liver microsomal fraction, α-hydroxylation yielded predominantly the 1′R-hydroxy product, 1′R 1′S ratio > 12, regardless of the stereochemistry of the side chain. In humans (extensive metabolizers) administered a single 50 mg oral dose of pseudoracemic metoprolol tartrate, urinary α-hydroxymetoprolol (2) accounted for 9.3 ± 2.4% of the dose, 2R 2S ratio of 0.85 ± 0.14, and the carboxylic acid metabolite 4, accounted for 52.7 ± 6.8% of the dose, 2R 2S ratio 1.15 ± 0.09. The data suggested that preferential O-demethylation of the (2R)-enantiomer of 1 could contribute to the 2S > 2R plasma ratio of metoprolol enantiomers observed in this population. © 1990.