Biotransformation of indomethacin by the fungus Cunninghamella blakesleeana  

作　　者：Peng ZHANG Li-hong LIN Hai-hua HUANG Hai-yan XU Da-fang ZHONG 

机构地区：[1]Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, Shenyang 110016, China [2]Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [3]Department of Microbiology, Shenyang Pharmaceutical University, Shenyang 110016, China

出　　处：《Acta Pharmacologica Sinica》2006年第8期1097-1102,共6页中国药理学报（英文版）

基　　金：Project supported by the National High Technology Research and Development Program of China(№ 2003AA2Z347C).

摘　　要：Aim： 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. 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 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/MSn and NMR spectra. These three metabolites were separated 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： Odesmethylindomethacin （DMI, M 1, 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. Conclusion： C blakesleeana could be a useful tool for generating the mammalian phase Ⅰ metabolites of indomethacin.Aim： 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. 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 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/MSn and NMR spectra. These three metabolites were separated 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： Odesmethylindomethacin （DMI, M 1, 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. Conclusion： C blakesleeana could be a useful tool for generating the mammalian phase Ⅰ metabolites of indomethacin.

关 键 词：INDOMETHACIN microbial transformation Cunninghamella blakesleeana liquid chromatography mass spectrometry 

分 类 号：R97[医药卫生—药品]