Biotransformation of indomethacin by the fungus Cunninghamella blakesleeana.

To investigate the biotransformation of indomethacin, the first of the newer nonsteroidal anti-inflammatory drugs, by filamentous fungus and to compare the similarities between microbial transformation and mammalian metabolism of indomethacin. Five strains of Cunninghamella (C elegans AS 3.156, C elegans AS 3.2028, C blakesleeana AS 3.153, C blakesleeana AS 3.910 and C echinulata AS 3.2004) were screened for their ability to catalyze the biotransformation of indomethacin. Indomethacin was partially metabolized by five strains of Cunninghamella, and C blakesleeana AS 3.910 was selected for further investigation. Three metabolites produced by C blakesleeana AS 3.910 were isolated using semi-preparative HPLC, and their structures were identified by a combination analysis of LC/MS(n) and NMR spectra. These three metabolites were separated and quantitatively assayed by liquid chromatography-ion trap mass spectrometry. After 120 h of incubation with C blakesleeana AS 3.910, approximately 87.4% of indomethacin was metabolized to three metabolites: O-desmethylindomethacin (DMI, M1, 67.2%), N-deschlorobenzoylindomethacin (DBI, M2, 13.3%) and O-desmethyl-N-deschlorobenzoylindomethacin (DMBI, M3, 6.9%). Three phase I metabolites of indomethacin produced by C blakesleeana AS 3.910 were identical to those obtained in humans. C blakesleeana could be a useful tool for generating the mammalian phase I metabolites of indomethacin.