Butixocort propionate

The disposition of butixocort 21-propionate (JO 12222, I) 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 μg 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 i.v. 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-Me (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 h.BDP was hydrolyzed rapidly into its active metabolite BMP after intratracheal and i.v. treatments; BDP was not observed in plasma after oral treatment.Addnl., 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 ∼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.Aerosol treatment with JO 12222 resulted in very low plasma concentrations of JO 1604, with an AUC value 15 and 45 times lower than that of BUD and BMP, resp.The three active compounds JO 1222, JO 1717, and JO 1605 were not detected in plasma after oral treatment.Together, these results show that the systemic clearance rates of unchanged JO 1222 and its metabolites are much higher than those of BUD and BDP.Such clearance rates could lead to a lower incidence of untoward side effects, rendering JO 1222 a favorable therapeutic profile for indications where corticosteroids need to be administered by aerosol inhalation.