Bioconversão e degradação da venlafaxina em seu metabólito ativo

• Autor(a) principal: Carneiro, Wilsione José
• Data de Publicação: 2010
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Repositório Institucional da UFG
• dARK ID: ark:/38995/001300000dsq5
• Texto Completo: http://repositorio.bc.ufg.br/tede/handle/tede/12524
• topic: Bioconversão; Estudo de degradação forçada; Venlafaxina; Produtos funcionalizados; Produtos de degradação; Bioconversion; Forced degradation study; Venlafaxine; Functionalized products; Degradation products; CIENCIAS BIOLOGICAS::FARMACOLOGIA::FARMACOLOGIA GERAL

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%).