Budesonide is retained in the airways longer than mometasone furoate due to the reversible formation of lipophilic budesonide fatty acid esters - significance for asthma therapy
K. Lexmuller, H. Falk Nilsson, R. Brattsand, A. Miller-Larsson (Lund, Sweden)
Source: Annual Congress 2002 - Asthma - Therapy and management -3
Session: Asthma - Therapy and management -3
Session type: Thematic Poster Session
Number: 444
Disease area: Airway diseases
Abstract Introduction: Budesonide (BUD) inhaled once-daily is effective in mild-moderate asthma, supporting a prolonged therapeutic effect on the airways. We have earlier shown that BUD has a longer dwell-time and anti-inflammatory activity in airway tissue than the more lipophilic fluticasone propionate.Aims: To compare the airway retention of BUD with that of the more lipophilic mometasone furoate (MF) and investigate the role of BUD endogenous esterification with fatty acids on BUD retention.Methods: Rat tracheas were preincubated for 15 min with the esterification inhibitor cyclandelate (CD) 10-3 mol/L or vehicle. 3 H-BUD or 3 H-MF (10-7 mol/L) was added for 20 min to determine steroid uptake. Tracheas were cut into halves, and one half was placed in fresh drug-free buffer for 3 h to monitor steroid release. BUD/BUD-esters and MF were analyzed in both halves.Results: The uptakes of BUD and MF into trachea were similar. However, MF release was more rapid (area-under-release-curve [AUC] 24% higher than for BUD [p=0.0002]). Only intact BUD was released from trachea (30% of BUD-esters were hydrolyzed during the release process). After release, total BUD concentration in the trachea was 3.6-fold higher than that of MF (p=0.0003). CD did not affect the uptake of steroids but decreased the fraction of lipophilic BUD-ester from 36% to 11% (p<0.0001). CD, by inhibiting BUD esterification, accelerated BUD release increasing AUC by 27% (p<0.0001), whereas it had no effect on MF release.Conclusions: Budesonide is retained in airway tissue longer than mometasone furoate due to the formation of lipophilic, slowly hydrolyzed budesonide-esters. Esterification of budesonide may account for its efficacy when inhaled once-daily.
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K. Lexmuller, H. Falk Nilsson, R. Brattsand, A. Miller-Larsson (Lund, Sweden). Budesonide is retained in the airways longer than mometasone furoate due to the reversible formation of lipophilic budesonide fatty acid esters - significance for asthma therapy. Eur Respir J 2002; 20: Suppl. 38, 444
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