The physiological disposition of aerosolized 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl]-gamma -oxobenzenebutanoate (L-648,051) in rats.
14C-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.
Tocco
D J
DJ
Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
Duncan
A E
AE
deLuna
F A
FA
Wells
G
G
D000336:Aerosols; D000818:Animals; D001711:Biotransformation; D002250:Carbon Radioisotopes; D007651:Keto Acids; D008168:Lung / Q000378:metabolism*; D008297:Male; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013450:Sulfones; D014018:Tissue Distribution; D014132:Trachea / Q000378:metabolism*
D000336:Aerosols; D002250:Carbon Radioisotopes; D007651:Keto Acids; D010654:Phenylbutyrates; D013450:Sulfones; C052024:L 648051