Vol. 30, Issue 11, 1274-1279, November 2002

Biotransformation of Mirtazapine by Cunninghamella Elegans

Joanna D. Moody, James P. Freeman, Peter P. Fu, and Carl E. Cerniglia

Division of Microbiology (J.D.M., C.E.C.), Division of Chemistry (J.P.F.), and Division of Biochemical Toxicology (P.P.F.), National Center for Toxicological Research, Jefferson, Arkansas

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, and N-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, the S(+)-enantiomer produced all seven metabolites whereas the R()-enantiomer produced only 8-hydroxymirtazapine, N-desmethyl-8-hydroxymirtazapine, N-desmethylmirtazapine, and mirtazapine N-oxide. C. elegans produced five mammalian and two novel metabolites and is therefore a suitable microbial model for mirtazapine metabolism.