title: Enantioselective and diastereoselective aspects of the oxidative metabolism of metoprolol.
abstract: 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 alpha-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, alpha-hydroxylation yielded predominantly the 1'R-hydroxy product, 1'R/1'S ratio greater than 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 alpha-hydroxymetoprolol (2) accounted for 9.3 +/- 2.4% of the dose, 2R/2S ratio 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 greater than 2R plasma ratio of metoprolol enantiomers observed in this population.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
authors.forename: S S
authors.initials: SS
authors.lastname: Murthy
authors.forename: H U
authors.initials: HU
authors.lastname: Shetty
authors.forename: W L
authors.initials: WL
authors.lastname: Nelson
authors.forename: P R
authors.initials: PR
authors.lastname: Jackson
authors.forename: M S
authors.initials: MS
authors.lastname: Lennard
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008745:Methylation; D008790:Metoprolol / Q000493:pharmacokinetics* / Q000652:urine; D008862:Microsomes, Liver / Q000378:metabolism*; D010101:Oxygen Consumption; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
chemical_list: D008790:Metoprolol