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 i.v. 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 with that in rat. MET1, the most polar metabolite, was the major metabolite in rat liver fractions, whereas 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-(3)H]MF revealed that most of the radioactivity (approximately 90%) was present in the stomach, intestines, and intestinal contents, suggesting biliary excretion of MF and its metabolites. Radiochromatography showed that most radioactivity was associated with MET1, MET2, and MET 3. Fractionation of the high-performance liquid chromatography eluate (MET1-5) revealed that only MF [relative binding affinity (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.