Biotransformation of doxepin by Cunninghamella elegans

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 the trans- (E) and cis- (Z) ratio of doxepin was observed. Metabolites were isolated by reversed phase HPLC and identified by (1)H 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.