Received for publication June 1, 2005.
Revised October 25, 2005.
Accepted for publication October 25, 2005.

Metabolism of Mometasone Furoate and Biological Activity of the Metabolites

Abstract

In order to better evaluate the pharmacokinetic and pharmacodynamic properties of the new inhaled glucocorticoid mometasone furoate (MF), the metabolism of MF was evaluated in rat and human tissues and in rat after iv administration. Metabolic studies with ³H-MF in human and rat plasma and S9 fractions of human and rat lung showed relatively high stability, and a degradation pattern similar to that seen in buffer systems. MF was efficiently metabolized into at least five metabolites in S9 fractions of both rat and human liver. There were, however, quantitative differences in the metabolites between the two species. The apparent half-life of MF in the S9 fraction of human liver was found to be 3 times greater compared to that in rat. MET1, the most polar metabolite, was the major metabolite in rat liver fractions where as both MET1 and MET2 were formed to an equal extent in human liver. Metabolism and distribution studies in rats after intravenous and intratracheal administration of [1,2-³H]-MF revealed that most of the radioactivity (90%) was present in the stomach, intestines and the intestinal contents, suggesting biliary excretion of MF and its metabolites. Radiochromatography showed that most radioactivity was associated with MET1, MET2 and MET3. Fractionation of the HPLC-eluate (MET1-5) revealed that only MF (RBA 2900) and MET2 (RBA 700) had appreciable glucocorticoid receptor binding affinity. These results suggest that MF undergoes distinct extrahepatic metabolism, but generates active metabolites that might be in part responsible for the systemic side effects of MF.

Key words: biliary excretion, metabolite identification, microsomes, pharmacokinetics, plasma protein binding