Pharmacokinetics of butixocort 21-propionate, budesonide, and beclomethasone dipropionate in the rat after intratracheal, intravenous, and oral treatments.
The disposition of butixocort 21-propionate (JO 1222) in the rat after intratracheal treatment with a pulmonary aerosol was compared to that of budesonide (BUD) and beclomethasone dipropionate (BDP) using tritium-labeled aerosols. Each aerosol canister delivered 50 micrograms of 3H-labeled steroid through an intratracheal catheter directly into the lung. Rats were sacrificed at different times after treatment. Lung and plasma concentrations of unchanged drug and active metabolites were measured by HPLC using a radioactivity detector. Tritium-labeled drugs (1.5 mg/kg) also were administered by the iv and oral routes for the purpose of comparing their systemic availability. The extent of biotransformation of all three steroids in the lung was very limited. JO 1222 was metabolized to the active compounds butixocort (JO 1717) and butixocort 21-methyl (JO 1605). BDP was transformed primarily to beclomethasone monopropionate (BMP); BUD was not metabolized in the lung. In contrast to these results, large differences were observed between plasma concentrations and systemic availability of the three drugs. BUD was rapidly absorbed from the lung, and its plasma elimination half-life was about 3 hr. BDP was hydrolyzed rapidly into its active metabolite BMP after intratracheal and iv treatments; BDP was not observed in plasma after oral treatment. Additionally, plasma concentrations of BMP were higher than those of BUD administered at the same doses. Assuming that BDP was transformed entirely into BMP, the oral bioavailability of BMP at 1.5 mg/kg was around 72%, while that of BUD was 15%. JO 1222 has a distinct pharmacokinetic profile due to the extensive metabolic clearance of both the unchanged drug and its active metabolites JO 1717 and JO 1605.(ABSTRACT TRUNCATED AT 250 WORDS)
Chanoine
F
F
Institut de Recherche Jouveinal, Fresnes, France.
Grenot
C
C
Heidmann
P
P
Junien
J L
JL
D000042:Absorption; D000280:Administration, Inhalation; D000284:Administration, Oral; D000287:Administration, Topical; D000336:Aerosols; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D001507:Beclomethasone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D019819:Budesonide; D002851:Chromatography, High Pressure Liquid; D005938:Glucocorticoids; D007275:Injections, Intravenous; D008297:Male; D011282:Pregnenediones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
D000336:Aerosols; D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D011282:Pregnenediones; D019819:Budesonide; C069739:butixocort 21-propionate; D001507:Beclomethasone