Fungal biotransformation of mosapride by Cunninghamella elegans

The filamentous fungus, Cunninghamella elegans AS 3.156, was used as a microbial model of mammalian metabolism to transform mosapride, a selective 5-HT4-receptor agonist. The fungal metabolites of mosapride were separated and detected by ultra performance liquid chromatography-tandem mass spectrometric method. After incubation for 120h, the parent drug was metabolized to thirteen metabolites, one of which was known major mammalian metabolite, des-p-fluorobenzyl mosapride, while the others were all novel metabolites. Four major metabolites including three new metabolites and one known major metabolite in mammals were isolated using preparative high-performance liquid chromatography and identified by 1D- and 2D-nuclear magnetic resonance, mass and UV spectroscopic analysis. Other metabolites were characterized according to their chromatographic behavior, mass and UV spectral data. The major metabolic pathways of mosapride transformed by the fungus were N-oxidation, morpholinyl ring cleavage, N-dealkylation of p-fluorobenzyl and further N-formylation, while minor metabolic pathways were N-dealkylation, glucoside conjugation. sulfate conjugation, formylation and N-dealkylation of the morpholinyl ring opened metabolite, N-dealkylation followed by acetylation. The fungi belonging to Cunninghamella species could not only be used to generate mammalian metabolites of mosapride in microgram scale, but also facilitate the production of putative metabolites or novel drug derivatives. The isolates could be used as reference standards for identification and analytical tests of mammalian metabolites of mosapride. (C) 2009 Elsevier B.V. All rights reserved.