Abstract

Chemical aspects of the major oxidative metabolic pathways of the beta-adrenergic blockers propranolol, metoprolol and bufuralol will be investigated. Structural and mechanistic chemical and stereochemical aspects of these processes will be examined. The major pathways to be explored are aromatic hydroxylation, including multiple hydroxylations, and the multistep N-dealkylation processes for propranolol; the alpha- hydroxylation (benzylic), O-demethylation and subsequent oxidation for metoprolol; and the benzylic hydroxylation of bufuralol. Some potential metabolites will be synthesized, and identification will be accomplished using the techniques of stable isotope labeling, hplc separation and GC-mass spectral determination. Stereochemical aspects of these pathways will be studied using the individual enantiomers and pseudoracemates of propranolol, racemic propranolol, enantiomers and pseudoracemates of metoprolol and of bufuralol. Experiments will be done in vitro (fractions from rat homogenates and human liver) and in vivo (in rats). Limited experiments in human subjects are proposed.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM025373-09
Application #
3272970
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1978-12-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
9
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
University of Washington
Department
Type
Schools of Pharmacy
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Dumas, J J; Zhu, Z; Connolly, J L et al. (1999) Structural basis of activation and GTP hydrolysis in Rab proteins. Structure 7:413-23
Piknova, B; Marsh, D; Thompson, T E (1996) Fluorescence-quenching study of percolation and compartmentalization in two-phase lipid bilayers. Biophys J 71:892-7
Murthy, S S; Nelson, W L; Shen, D D et al. (1991) Pharmacokinetic interaction between verapamil and metoprolol in the dog. Stereochemical aspects. Drug Metab Dispos 19:1093-100
Weerawarna, S A; Geisshusler, S M; Murthy, S S et al. (1991) Enantioselective and diastereoselective hydroxylation of bufuralol. Absolute configuration of the 7-(1-hydroxyethyl)-2-[1-hydroxy-2-(tert-butylamino)ethyl]benzofurans, the benzylic hydroxylation metabolites. J Med Chem 34:3091-7
Murthy, S S; Shetty, H U; Nelson, W L et al. (1990) Enantioselective and diastereoselective aspects of the oxidative metabolism of metoprolol. Biochem Pharmacol 40:1637-44
Shetty, H U; Nelson, W L (1988) Chemical aspects of metoprolol metabolism. Asymmetric synthesis and absolute configuration of the 3-[4-(1-hydroxy-2-methoxyethyl)phenoxy]-1-(isopropylamino)-2-propanols , the diastereomeric benzylic hydroxylation metabolites. J Med Chem 31:55-9
Gustavson, L M; Nelson, W L (1988) Regioisomeric products of propranolol metabolism. The monomethyl ethers of 3,4-dihydroxypropranolol and of 3,4-dihydroxypropranolol glycol. Drug Metab Dispos 16:217-21
Talaat, R E; Nelson, W L (1988) Regioisomeric aromatic dihydroxylation of propranolol. Use of monohydroxylated intermediates for structural assignments of the metabolites formed in vitro. Drug Metab Dispos 16:207-11
Talaat, R E; Nelson, W L (1988) Regioisomeric aromatic dihydroxylation of propranolol. Synthesis and identification of 4,6- and 4,8-dihydroxypropranolol as metabolites in the rat and in man. Drug Metab Dispos 16:212-6
Shetty, H U; Nelson, W L (1986) Chemical and stereochemical aspects of propranolol metabolism. Diastereomeric 1-(1-hydroxy-2-propylamino)-3-(1-naphthoxy)-2-propanols produced by rat liver microsomal omega-hydroxylation. J Med Chem 29:2004-8

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