Biotransformation of indomethacin by the fungus Cunninghamella blakesleeana.
OBJECTIVE
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/MS(n) 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: 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.


CONCLUSIONS
C blakesleeana could be a useful tool for generating the mammalian phase I metabolites of indomethacin.
Zhang
Peng
P
Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, Shenyang 110016, China.
Lin
Li-Hong
LH
Huang
Hai-Hua
HH
Xu
Hai-Yan
HY
Zhong
Da-Fang
DF
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D001711:Biotransformation; D002853:Chromatography, Liquid; D020093:Cunninghamella / Q000378:metabolism*; D007210:Indoleacetic Acids / Q000378:metabolism; D007213:Indomethacin / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007210:Indoleacetic Acids; C034674:5-hydroxyindomethacin; C030098:5-methoxy-methylindoleacetic acid; D007213:Indomethacin