Biotransformation of doxepin by Cunninghamella elegans

A filamentous fungus, Cunninghamella elegans ATCC 9245, was used as a micro bial model of mammalian metabolism to biotransform doxepin, a tricyclic ant idepressant 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 b y reversed phase HPLC and identified by H-1 NMR and mass spectroscopic anal ysis. 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-for myldoxepin, (E)-N-acetyldidesmethyldoxepin, (E)- and (Z)-doxepin-N-oxide, a nd (E)- and (Z)-N-desmethyldoxepin. Six of the metabolites produced by C. e legans were essentially similar to those obtained in human metabolism studi es, although nine novel metabolites were identified.