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Abstract

OPTIMIZATION STUDIES FOR CLOZAPINE BIOTRANSFORMATION TO ITS ACTIVE METABOLITE - NORCLOZAPINE USING FUNGI.

S. Varalaxmi and M. Vidyavathi*

Abstract

Clozapine is an antipsychotic drug which is used for treatment of schizophrenia. It is metabolised by CYP1A2 enzyme to its active metabolite norclozapine in human beings. The biotransformation of clozapine was performed by eight strains of fungi using fermentation technique and HPLC analysis. Among which a filamentous fungus Cunninghamella elegans has shown ability to biotransform clozapine to its active metabolite, norclozapine which was identified by HPLC, Mass spectroscopy and 1HNMR studies. Then the influence of different parameters like change in media components such as carbon and nitrogen sources used in media, incubation period and agitation speeds on metabolite production was investigated and also their respective cell dry weights were determined during optimization studies. Among different carbon and nitrogen sources used, maximum metabolite was formed when dextrose and yeast extract were used as carbon and nitrogen sources respectively. The influence of different concentrations of dextrose and yeast on the metabolite production was also investigated. Maximum biotransformation was observed at 2% dextrose, 0.001% yeast extract, 48th hour of incubation period and at 120 rpm. Based upon the results, it can be concluded that there is an influence of media components and their concentration, incubation period and agitation speeds on extent of biotransformation of clozapine to its active metabolitenorclozapine by fungus. Optimized conditions were determined in present study for maximum production of norclozapine.

Keywords: Clozapine, fungal biotransformation, active metabolite, norclozapine, Cunninghamella elegans.


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