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 3 H-GC (ϳ10 ؊7 M: BUD, CIC, CIC-AM, FP, MF) was added for 20 min.After incubation, one half of the trachea was used for analysis of GC uptake and the other to analyze GC release during 3 h in drug-free medium. GC species in trachea halves were analyzed by radiochromatography. At 20 min, the uptake of BUD was similar to that of CIC/CIC-AM; however, the BUD-ester pool was 9-fold greater (p < 0.01). BUD overall retention in trachea at 3 h was greater than that of other GCs (p < 0.01), and the BUD-ester pool was 3-fold greater than the 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 h (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, similar to FP and MF, which are not esterified.

In the present study we have investigated the effect of L-nitro arginine mono methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase on Sephadex induced inflammation in the rat lung. Instillation of Sephadex into the airways induced an inflammatory reaction characterized by a long-lasting interstitial oedema, measured as an increase in lung weight, and an influx of inflammatory cells into the airways. L-NAME given s.c. prevented the increase in lung weight following Sephadex instillation. The inactive enantiomer D-NAME had no effect, nor did aminoguanidine which indicates that this effect of L-NAME was mediated by inhibition of the constitutive form of NOS. Treatment with L-NAME did not reduce an established oedema. In contrast, L-NAME tended to enhance the influx of oesinophils into the airways of Sephadex-instilled animals. L-NAME did not have any effect on the development of oedema in adrenalectomized rats or in animals where formation of glucocorticosteroids (GCS) was inhibited with metyrapone. L-NAME did not however, increase plasma levels of corticosterone. The present results indicate that, in this model, inhibition of NO-synthesis has marked anti-inflammatory effects. The underlying mechanism is complex but seems not to involve prevention of overproduction of NO.