Bioconversão e degradação da venlafaxina em seu metabólito ativo
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2010-03-03
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Universidade Federal de Goiás
Resumo
The venlafaxine, 1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl] cyclohexanol, is a
antidepressant drug of second generation. This is one of the most potent reuptake
inhibitor of serotonin and noradrenaline, and its therapeutic effect is attributed to this
activity. Venlafaxine is biotransformed in the liver to O-desmethylvenlafaxine
(desvenlafaxine), N, O-desmethylvenlafaxine, N-desmethylvenlafaxine. Enzymes
CYP2D6, CYP2C19 and CYP2C9 metabolize venlafaxine and major metabolite is the O desmethylvenlafaxine. This is pharmacologically active and contributes significantly to
the pharmacological effect of venlafaxine, as is found in plasma at high concentrations.
The investigation of the formation of degradation products is of great importance,
because the products formed may be less active, more active or toxic. Bioconversion or
the application of microbial models is a strategy to mimic the mammalian metabolism
produces significant quantities of metabolites for studies of pharmacological activity and
toxicological. This work represents a forced degradation study of venlafaxine extended release capsules in different stress conditions (acid and alkaline hydrolysis, oxidative
and thermal) and select strains of filamentous fungi, to identify those able to metabolize
venlafaxine and produce in a semi-preparative major metabolites. The filamentous fungi
used were: Aspergillus candidus ATCC 2023, Beauveria bassiana ATCC 7159,
Cunninghamella echinulata ATCC 9244, Cunningamella elegans ATCC 6169,
Mortierella isabelina ATCC 1757 and Rhizopus arrhizus ATCC 11145. Was developed
and validated method stability indicating HPLC using reverse phase for the analysis of
venlafaxine in pharmaceutical formulation. The metabolites prepared by bioconversion
were used for structural elucidation and later as a reference chemical in the analysis of
stability studies and future studies of pharmacological and toxicological activity. The
fungus Cunninghamella elegans ATCC 6169 was selected and produced O desmethylvenlafaxine (desvenlafaxine) and dihydroxy-venlafaxine, similar to those
found in mammals, reinforcing the application of microbial models for the study of animal
metabolism. The study indicated the stability of the acid condition of venlafaxine, formed
two degradation products, the products found were similar to those obtained by
bioconversion. The O-desmethylvenlafaxine, corresponds to the active metabolite of
venlafaxine in humans and was recently approved for the treatment of major depressive
disorder. Those studies, one can get the O-desmethylvenlafaxine in bioconversion
reactions by Cunninghamella elegans ATCC 6169 and forced degradation studies of
venlafaxine. The method developed and validated HPLC method was considered
indicative of stability analysis of venlafaxine extended-release capsules, it is sensitive,
specific (interference < 2%), precise (RSD < 2%), linear (r > 0.99), accurate (98.0 to
102.0%) and reproducible (RSD < 2%).
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Citação
CARNEIRO, W. J. Bioconversão e degradação da venlafaxina em seu metabólito ativo. 2010. 76 f. Dissertação (Mestrado em Ciências Farmacêuticas) - Universidade Federal de Goiás, Goiânia, 2010.