Biotransformation of Mirtazapine byCunninghamella Elegans

Abstract

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, 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.The antidepressant drug mirtazapine (1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c]benzazepine), marketed as RE-MERON SolTab, has a tetracyclic chemical structure ( Fig. 1) that is unlike those of selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, or tricyclic antidepressants. It also has a different mode of action. Mirtazapine acts as an antagonist of ␣ 2 -adrenergic autoreceptors and heteroreceptors, resulting in increased release of norepinephrine and serotonin (Puzantian, 1998). Therefore, it has been regarded as a noradrenergic and specific serotonergic antidepressant (Westenberg, 1999). Mirtazapine is also an antagonist of postsynaptic serotonin type 2 (5-HT 2 ) 1 and type 3 (5-HT 3 ), but not type 1 (5-HT 1 ) receptors, decreasing unwanted side effects (Stimmel et al., 1997). The drug has a high affinity for histamine H 1 receptors, causing it to act as a sedative (Puzantian, 1998).Mirtazapine is commercially available as a racemic mixture of the S(ϩ)-and R(Ϫ)-enantiomers (Fig. 1). The S(ϩ)-enantiomer is responsible for blocking ␣ 2 activity and is the more potent 5-HT 2 antagonist (McGrath et al., 1998). The R(Ϫ)-enantiomer is responsible for the 5-HT 3 antagonist activity and contributes equally to the blocking of ␣ 2 -heteroreceptors (McGrath et al., 1998). Both enantiomers function as antihistamines (Stimmel et al., 1997).Since it is assumed that metabolism of this drug takes place mainly in the liver (Sandker et al., 1994), metabolic studies have been undertaken using human liver and rat hepatocytes and human liver microsomes (Sandker et al., 1994;Dahl et al., 1997). Phase I and II human metabolites reported were mirtazapine-N-oxide, 8-hydroxymirtazapine, N-desmethylmirtazapine, mirtazapine N-glucuronide, mirtazapine N-sulfate, 8-hydroxymirtazapine glucuronide, 8-hydroxy-N-desmethylmirtazapine, 8-hydroxy-N-desmethylmirtazapine glucuronide, 8-hydroxymirtazapine sulfate, and 8-hydroxy-N-desmethylmirtazapine sulfate. The same metabolites are also produced...

Transformation of Verapamil byCunninghamella blakesleeana

“…A major goal of studies on these microbial models is to develop a list of microorganisms that can mimic the metabolic profiles of drugs in mammals. Filamentous fungi from the genus Cunninghamella, particularly Cunninghamella elegans, often metabolize drugs in a manner similar to that in mammals (2,3,7,10,11,15,22).…”

“…A major goal of studies on these microbial models is to develop a list of microorganisms that can mimic the metabolic profiles of drugs in mammals. Filamentous fungi from the genus Cunninghamella, particularly Cunninghamella elegans, often metabolize drugs in a manner similar to that in mammals (2,3,7,10,11,15,22).Although the metabolism of verapamil in mammals has been studied, little is known about the potential of nonligninolytic fungi to metabolize verapmil. The objective of this paper is to identify a fungus that can extensively metabolize verapamil and to chemically identify the metabolites.…”

Biotransformation of Flurbiprofen by Cunninghamella Species

“…C. elegans DSM 1908 is well known as a model of mammalian drug metabolism (10,11), and analysis of the organically extractable metabolites by 19 F NMR spectroscopy using a Varian 400-MHz spectrometer revealed that flurbiprofen was completely degraded to one fluorometabolite over 3 days (Fig. 1).…”

Metabolite Generation via Microbial Biotransformations with Actinomycetes: Rapid Screening for Active Strains and Biosynthesis of Important Human Metabolites of Two Development-Stage Compounds, 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non7-yl-methyl]-3-thiophenecarboxylic Acid (BMS-587101) and Dasatinib

“…Work in this area has been reviewed (Abourashed et al, 1999;Azerad, 1999), and there has been an increasing number of reports describing the use of microbial systems to mimic or predict mammalian metabolite formation and to prepare larger quantities of mammalian metabolites (Moody et al, 1999(Moody et al, , 2002Xie et al, 2005;Zhang et al, 2006;Zmijewski et al, 2006). The traditional microbial screening methods using shake flasks are labor intensive, which has likely limited the widespread use of microbial biotransformation in drug metabolism studies.…”