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Publication
Impacto do microbioma intestinal na ação dos medicamentos
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Advisor(s)
Abstract(s)
O microbioma intestinal humano (MIH) consiste numa elevada diversidade de microrganismos e genes, que interagem entre si, com as restantes células do hospedeiro e com tudo aquilo que passa pelo intestino, incluindo medicamentos. A composição do MIH tanto pode ser influenciada por alguns medicamentos, tal como pode desempenhar um papel fundamental no metabolismo dos mesmos. A variabilidade inter- e intra-individual do MIH tem dificultado a compreensão do seu impacto na ação dos medicamentos. Contudo, na literatura atual há alguns exemplos bem documentados do impacto do MIH em algumas classes de medicamentos que importa conhecer. Neste contexto, o principal objetivo deste trabalho foi descrever o modo como o MIH pode interferir nos medicamentos, em particular ao nível da farmacocinética, mecanismo de ação e segurança. O objetivo secundário consistiu em analisar o impacto de alguns medicamentos, probióticos e prebióticos na composição do MIH. Para a elaboração desta dissertação, foram analisados cerca de 53 artigos publicados entre 2015 e 2020, nas seguintes bases de dados: PubMed, ScienceDirect, NCBI e Cochrane Library. O MIH interfere na ação de diversas classes terapêuticas, tendo demonstrado que as enzimas microbianas metabolizam medicamentos diretamente no TGI, através de reações bioquímicas, que desencadeiam: 1) transformação de pró-fármacos em fármacos ativos, como a sulfassalazina que é convertida em ácido 5-aminosalicílico por ação de azoredutases; 2) convertem fármacos ativos em compostos inativos, tal como a digoxina que é convertida em dihidrodigoxina por ação do operão cgr presente em Eggerthella lenta; 3) formação de metabolitos tóxicos, como o irinotecano que é convertido no seu metabolito ativo SN-38 por ação de β-glucuronidases, tornando-o enterotóxico. Concluindo, a compreensão da interação entre o MIH e os medicamentos é um processo que permitirá otimizar a eficácia dos medicamentos sem comprometer a sua segurança. Os resultados destas investigações terão importantes implicações para a atividade médica e farmacêutica.
The human gut microbiome (HGM) consists of a high diversity of microorganisms and their genes, that can interact with each other, host cells, and medicines. The composition of HGM can be influenced by drugs, as well as playing a fundamental role in their metabolism. The inter- and intra-individual variability of HGM has made it difficult to understand its impact on the action of medicines. However, there are some well-documented examples in the current literature about the impact of HGM on some classes of drugs that are important to know. In this context, this study aimed to describe how HGM can interfere with medicines, focusing in the pharmacokinetics properties, mechanism of action, and safety. The secondary objective was to analyze the impact of medicines, probiotics and prebiotics on the composition of HGM. Academic research comprises approximately 53 articles published between 2015 and 2020, from the following databases: PubMed, ScienceDirect, NCBI, and Cochrane Library. The HGM interferes with the action of several therapeutic classes, since previous works demonstrated that microbial enzymes metabolize drugs directly in the GIT, through biochemical reactions, that trigger: 1) transformation of prodrugs into active drugs, such as sulfasalazine which is converted into 5-aminosalicylic acid by the action of azoredutases; 2) convert active drugs into inactive compounds, for instance, digoxin is converted to dihydrodigoxin through the cgr operon present in Eggerthella lenta; 3) the transformation of toxic metabolites, such as irinotecan, which is converted into its active metabolite SN-38 by the action of β-glucuronidases, turning it enterotoxic. In conclusion, understanding the interaction between HGM and medicines will allow the optimization of the effectiveness of medicines without compromising their safety. The results of these investigations have important implications for medical and pharmaceutical activity.
The human gut microbiome (HGM) consists of a high diversity of microorganisms and their genes, that can interact with each other, host cells, and medicines. The composition of HGM can be influenced by drugs, as well as playing a fundamental role in their metabolism. The inter- and intra-individual variability of HGM has made it difficult to understand its impact on the action of medicines. However, there are some well-documented examples in the current literature about the impact of HGM on some classes of drugs that are important to know. In this context, this study aimed to describe how HGM can interfere with medicines, focusing in the pharmacokinetics properties, mechanism of action, and safety. The secondary objective was to analyze the impact of medicines, probiotics and prebiotics on the composition of HGM. Academic research comprises approximately 53 articles published between 2015 and 2020, from the following databases: PubMed, ScienceDirect, NCBI, and Cochrane Library. The HGM interferes with the action of several therapeutic classes, since previous works demonstrated that microbial enzymes metabolize drugs directly in the GIT, through biochemical reactions, that trigger: 1) transformation of prodrugs into active drugs, such as sulfasalazine which is converted into 5-aminosalicylic acid by the action of azoredutases; 2) convert active drugs into inactive compounds, for instance, digoxin is converted to dihydrodigoxin through the cgr operon present in Eggerthella lenta; 3) the transformation of toxic metabolites, such as irinotecan, which is converted into its active metabolite SN-38 by the action of β-glucuronidases, turning it enterotoxic. In conclusion, understanding the interaction between HGM and medicines will allow the optimization of the effectiveness of medicines without compromising their safety. The results of these investigations have important implications for medical and pharmaceutical activity.
Description
Dissertação para obtenção do grau de Mestre no Instituto Universitário Egas Moniz
Keywords
Microbioma Intestino Medicamento Metabolização