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Aim:To investigate the biotransformation of indomethacin,the first of the newernonsteroidal anti-inflammatory drugs,by filamentous fungus and to compare thesimilarities between microbial transformation and mammalian metabolism ofindomethacin.Methods:Five strains of Cunninghamella(C elegans AS 3.156,C elegans AS 3.2028,C blakesleeana AS 3.153,C blakesleeana AS 3.910 andC echinulata AS 3.2004)were screened for their ability to catalyze the biotransfor-mation of indomethacin.Indomethacin was partially metabolized by five strains ofCunninghamella,and C blakesleeana AS 3.910 was selected for furtherinvestigation.Three metabolites produced by C blakesleeana AS 3.910 wereisolated using semi-preparative HPLC,and their structures were identified by acombination analysis of LC/MS~n and NMR spectra.These three metabolites wereseparated and quantitatively assayed by liquid chromatography-ion trap massspectrometry.Results: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 blakesleeanaAS 3.910 were identical to those obtained in humans.Conclusion:C blakesleeanacould be a useful tool for generating the mammalian phase I metabolites ofindomethacin.
Aim: To investigate the biotransformation of indomethacin, the first of the newernonsteroidal anti-inflammatory drugs, and the first of the newernonsteroidal anti-inflammatory drugs, the microbial transformation and mammalian metabolism of indomethacin. Methods: 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 Cechinulata AS 3.2004) were screened for their ability to catalyze the biotransfor-mation of indomethacin. Indomethacin was partially metabolized by five strains of Cunninghamella, and C blakesleeana AS 3.910 was selected for further investigation. Thhtml metabolites produced by C blakesleeana AS 3.910 wereisolated using semi-preparative HPLC, and their structures were identified by acombination analysis of LC / MS ~ n and NMR spectra. These three metabolites were separately and quantitatively assayed by liquid chromatography-ion trap mass spectrometry. Results: 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 metabolites of indomethacin produced by C blakesleeana AS 3.910 were identical to those obtained in humans. Conlusion: C blakesleeanacould be a useful tool for generating the mammalian phase I metabolites ofindomethacin.