Abstract
A filamentous fungus, Cunninghamella elegans ATCC 9245, was used as a microbial model of mammalian metabolism to biotransform doxepin, a tricyclic antidepressant drug. Doxepin is produced as an 85:15% mixture of the trans- (E) and cis- (Z) forms. After 96 h of incubation in Sabouraud dextrose broth, 28% of the drug was metabolized to 16 metabolites. No change in thetrans- (E) and cis- (Z) ratio of doxepin was observed. Metabolites were isolated by reversed phase HPLC and identified by 1H NMR and mass spectroscopic analysis. The major metabolites were (E)-2-hydroxydoxepin, (E)-3-hydroxydoxepin, (Z)-8-hydroxydoxepin, (E)-2-hydroxy-N-desmethyldoxepin, (E)-3-hydroxy-N-desmethyldoxepin, (E)-4-hydroxy-N-desmethyldoxepin, (Z)- and (E)-8-hydroxy-N-desmethyldoxepin, (E)-N-acetyl-N-desmethyldoxepin, (E)-N-desmethyl-N-formyldoxepin, (E)-N-acetyldidesmethyldoxepin, (E)-and (Z)-doxepin-N-oxide, and (E)- and (Z)-N-desmethyldoxepin. Six of the metabolites produced by C. elegans were essentially similar to those obtained in human metabolism studies, although nine novel metabolites were identified.
Footnotes
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Send reprint requests to: Dr. Carl E. Cerniglia, Division of Microbiology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079-7341. E-mail:CCerniglia{at}nctr.fda.gov
- Abbreviations used are::
- NOE
- nuclear Overhauser effect
- DEP
- direct exposure probe
- EI
- electron ionization
- PICI
- positive ion chemical ionization
- Received March 3, 1999.
- Accepted June 10, 1999.
- U.S. Government
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