Degradation of mometasone furoate in the lung

Abstract Rationale The degradation of mometasone furoate (MF), a new inhaled glucocorticoid, in lung and simulated lung fluid has been recently described and potential degradation products have been suggested. As these studies were not definitive and because of the potential importance of pulmonary degradation on the activity of MF, we investigated the metabolism of MF in rat and human lung and in simulated lung fluid (SLF) and assessed the biological activities to the glucocorticoid receptor (GR). Methods MF was incubated in S9 fractions of rat and human lung and in SLF at 37°C. The degradation products were identified using LC-MS and NMR. Biological activity was assessed by performing rat lung GR binding studies. Results In SLF, MF degradation resulted in two products, D1 and D2. D1 was identified as 9,11-epoxide MF. D2 was a condensed product of MF, different from previously suggested MF degradation products. Incubation of MF in rat and human lung S9 fractions resulted in generation of D2 presumably through the formation of D1, indicating that the slow degradation of MF in the lung is non-enzymatic. D1 showed significant binding (IC 50 , 11 nM) to the GR that is comparable to other inhaled corticosteroids but is lower than MF (IC 50 , 1.6 nM). D2 did not bind to the GR (IC 50 >300 nM). Conclusions The pulmonary instability of MF is related to a relatively slow chemical degradation with one of the degradation products showing glucocorticoid receptor activity, the other representing a new cyclized structure. The biological significance of these metabolites is unknown.