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Disposition and metabolism of sodium 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl]-gamma -oxobenzenebutanoate in rats and dogs.

Abstract
The disposition of sodium 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl]-gamma-o xo benzenebutanoate (L-648,051) was determined in rats and dogs. L-648,051 is a potent receptor antagonist for leukotriene D4 and is potentially useful in the treatment of asthma and other allergic disorders. After a dosage of 10 mg/kg iv, L-648,051 declined rapidly with a half-life of approximately 2 min in rat and dog plasma. Although the compound was well absorbed, it exhibited poor bioavailability due to efficient first-pass metabolism. In rats receiving 25, 50, and 150 mg/kg po, bioavailabilities were 0.5, 4.8, and 38.7%, respectively. In dogs, bioavailability of 10 and 50 mg/kg po was 0 and 23%, respectively. Two metabolites were identified, 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl-gamma- hydroxybenzenebutanoic acid (metabolite I), formed by ketoreduction, and 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl] benzeneacetic acid (metabolite II) formed by catabolic oxidation of the butanoic acid moiety of L-648,051. Ketoreduction resulted in the production of a chiral center and two enantiomers of metabolite I. In vitro studies suggest that rat erythrocytes formed the (+)-enantiomer exclusively. When L-648,051 was administered orally or iv to rats, both the (+)- and (-)-enantiomers were observed in the plasma. The data suggest that either two L-648,051 ketoreductases were present or that inversion of the hydroxyl stereocenter of metabolite I occurred.
AuthorsD J Tocco, F A deLuna, A E Duncan, H G Ramjit, S M Pitzenberger, J Y Hsieh
JournalDrug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) 1988 Sep-Oct Vol. 16 Issue 5 Pg. 690-6 ISSN: 0090-9556 [Print] United States
PMID2906591 (Publication Type: Journal Article)
Chemical References
  • Carbon Radioisotopes
  • Keto Acids
  • Phenylbutyrates
  • Sulfones
  • L 648051
Topics
  • Animals
  • Bile (metabolism)
  • Biotransformation
  • Carbon Radioisotopes
  • Chromatography, High Pressure Liquid
  • Dogs
  • Female
  • Keto Acids
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Male
  • Mass Spectrometry
  • Phenylbutyrates (blood, metabolism, pharmacokinetics)
  • Rats
  • Rats, Inbred Strains
  • Species Specificity
  • Sulfones

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