ENZYME INDUCTION AND INHIBITION STUDIES FOR FUNGAL BIOTRANSFORMATION OF LORATADINEM. KEERTHANA AND M. VIDYAVATHI
Fungi have great potential for biotransformation of many substrates into the desired metabolite products especially for development of new therapeutically active ingredients. Loratadine, an azatadine derivative and tricyclic antihistaminic drug. CYP3A4 and CYP2D6 are major metabolising isoenzymes involved in the hepatic metabolism of loratadine. An active metabolite formed after the metabolism is desloratadine, which is as effective as loratadine. Hence, preliminary screening studies were conducted for biotransformation of loratadine using six fungi. Among six fungi, two fungi i.e., Cunnighmella elegans and Aspergillus niger were found to be capable of transform the loratadine to its metabolite. Then, the fungal enzyme involved in this biotransformation of loratadine was planned to determine by induction and inhibition studies. The aim of the present study was to confirm whether CYP 3A4 or CYP 2D6 like enzyme is responsible for fungal biotransformation of loratadine using their inducers and inhibitors. It was conducted using fermentation by incubating the organism in presence of drug and inhibitor, drug and inducer separately along with their individual controls. The metabolite formed in absence and presence of inducer or inhibitor was estimated quantitatively using HPLC analysis. The results of the present work have shown increased percentage of metabolite formation in presence of CYP 3A4 inducer and decreased percentage of metabolite formation in presence CYP3A4 inhibitor with Aspergillus niger, which proved that, the influence of CYP3A4 like enzyme in biotransformation of loratadine by Aspergillus niger. Whereas, in case of, Cunnighmella elegans there was no significant change observed in the percentage of metabolite formation in presence of CYP 3A4 inducer and inhibitor. But, increased percentage of metabolite formation in presence CYP 2D6 inducer and decreased percentage of metabolite formation in presence CYP2D6 inhibitor with Cunnighmella elegans was observed. This confirmed that, the role of CYP2D6 like enzyme in biotransformation of loratadine by Cunnighmella elegans. These studies revealed that Aspergillus niger is able to metabolize the drug analogus to human metabolism reactions mediated by CYP3A4 and Cunnighmella elegans is able metabolise by CYP 2D6 like enzyme. Hence, the present study concluded that Aspergillus niger can be used as a model for CYP3A4 enzyme and Cunnighmella elegans can be used as a model for CYP 2D6 enzyme in biotransformation of other drugs.
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