Abstract

The fungus Cunninghamella elegans was used as a microbial model of mammalian metabolism to biotransform the tetracyclic antidepressant drug mirtazapine, which is manufactured as a racemic mixture of R(−)- and S(+)-enantiomers. In 168 h, C. elegans transformed 91% of the drug into the following seven metabolites: 8-hydroxymirtazapine,N-desmethyl-8-hydroxymirtazapine,N-desmethylmirtazapine, 13-hydroxymirtazapine, mirtazapine N-oxide, 12-hydroxymirtazapine, andN-desmethyl-13-hydroxymirtazapine. Circular dichroism spectral analysis of unused mirtazapine indicated that it was slightly enriched with the R(−)-enantiomer. When the fungus was treated with the optically pure forms of the drug, theS(+)-enantiomer produced all seven metabolites whereas the R(−)-enantiomer produced only 8-hydroxymirtazapine,N-desmethyl-8-hydroxymirtazapine,N-desmethylmirtazapine, and mirtazapineN-oxide. C. elegans produced five mammalian and two novel metabolites and is therefore a suitable microbial model for mirtazapine metabolism.