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First published on July 12, 2007; DOI: 10.1124/dmd.107.015297

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Received for publication February 21, 2007.
Revised July 7, 2007.
Accepted for publication July 9, 2007.

Differences in endogenous esterification and retention in the rat trachea between budesonide and ciclesonide active metabolite

Kristina Lexmuller 1, Helena Gullstrand 1, Bengt-Olof Axelsson 1, Petter Sjolin 1, Solange H Korn 1, David S Silberstein 1, Anna Miller-Larsson 1*

1 AstraZeneca R&D Lund

* Address correspondence to: E-mail: anna.miller-larsson{at}astrazeneca.com

Abstract

The airway retention of inhaled glucocorticosteroids (GCs) depends largely on their lipophilicity. Inhaled budesonide (BUD) becomes highly lipophilic reversibly by the formation of esters, acting as a reservoir of active BUD. Ciclesonide (CIC) was also reported to form esters after hydrolysis to active metabolite (CIC-AM). We have investigated lipophilicity and airway retention of BUD, CIC/CIC-AM, fluticasone propionate (FP) and mometasone furoate (MF), and compared esterification of BUD and CIC-AM and its contribution to GC airway retention. Rat tracheas were preincubated with the esterification inhibitor cyclandelate or vehicle. A 3H-GC (~10-7M: BUD, CIC, CIC-AM, FP, MF) was added for 20 min. After incubation, one half of trachea was used for analysis of GC uptake and the other to analyse GC release during 3 hours in drug-free medium. GC species in trachea halves were analysed by radiochromatography. At 20 min the uptake of BUD was similar to CIC/CIC-AM, however BUD-ester pool was 9-fold greater (p<0.01). BUD overall retention in trachea at 3 hours was greater than other GCs (p<0.01), and BUD-ester pool was 3-fold greater than CIC-AM-ester pool (p<0.01). Cyclandelate decreased the initial BUD- and CIC-AM-ester pools (p<0.01), and reduced the overall retention of BUD at 3 hours (p<0.01) but not of CIC-AM. Thus, BUD becomes esterified in the airways more promptly and to a greater extent than CIC-AM, and BUD esterification prolongs BUD airway retention. In contrast, airway retention of CIC-AM and CIC seems to be determined mainly by their lipophilicity, similarly to FP and MF that are not esterified.


Key words: anti-inflammatory drugs, clinical pharmacokinetics, clinical pharmacology, drug disposition, inhaled drugs, pharmacokinetics, pulmonary metabolism, pulmonary pharmacology, respiratory pharmacology, steroids




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