Physiological disposition of aerosolized 4-((3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl)-gamma -oxobenzenebutanoate (L-648,051) in rats

Journal Article · Thu Sep 01 04:00:00 EDT 1988 · Drug Metab. Dispos.; (United States)

OSTI ID:6075421

Tocco, D J; Duncan, A E; deLuna, F A; Wells, G

/sup 14/C-labeled 4-((3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)-sulfonyl)-gamma- oxobenzenebutanoate (L-648,051) was suspended in Freon under pressure and injected into rat lungs via a tracheal cannula. The particle size of the drug was 1 to 5 microns and the mean dose was approximately 0.2 mg/kg. Levels of radioactivity in the lung/trachea declined in a monoexponential manner. Absorption, estimated from radioactivity remaining in the lung and trachea, was 73% in 1 hr and 95% in 4 hr. L-648,051 and its pharmacologically active metabolite L-657,098 (formed by ketoreduction of the butanoic acid moiety of L-648,051) accounted for 96% of the radioactivity in the lung at 10 min after the dose and 91% after 60 min. The lung:plasma concentration ratio of active drug (L-648,051 plus L-657,098) was at least 176:1 at 10 min and 17:1 at 60 min (compared with 1:1 after 2 mg/kg iv) suggesting that aerosol administration of L-648,051 in humans may result in an ideal therapeutic ratio, with high levels of pharmacologically active ingredient in the lung and low levels in the plasma.

• Research Organization: Merck Sharp and Dohme Research Laboratories, West Point, PA (USA)
• OSTI ID: 6075421
• Journal Information: Drug Metab. Dispos.; (United States), Journal Name: Drug Metab. Dispos.; (United States) Vol. 16:5; ISSN DMDSA
• Country of Publication: United States
• Language: English

Related Subjects

550501* -- Metabolism-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AEROSOLS
ANIMALS
BIOLOGICAL MATERIALS
BLOOD
BLOOD PLASMA
BODY
BODY FLUIDS
BUTYRIC ACID
CARBON 14 COMPOUNDS
CARBOXYLIC ACIDS
COLLOIDS
DISPERSIONS
DISTRIBUTION
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
LUNGS
MAMMALS
MATERIALS
METABOLISM
MONOCARBOXYLIC ACIDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PARTICLE SIZE
RATS
RESPIRATORY SYSTEM
RODENTS
SIZE
SOLS
TISSUE DISTRIBUTION
TRACER TECHNIQUES
TRACHEA
VERTEBRATES