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.
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Authors | D J Tocco, F A deLuna, A E Duncan, H G Ramjit, S M Pitzenberger, J Y Hsieh |
Journal | Drug 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 |
PMID | 2906591
(Publication Type: Journal Article)
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Chemical References |
- Carbon Radioisotopes
- Keto Acids
- Phenylbutyrates
- Sulfones
- L 648051
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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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