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BSEP drug inhibition and cholestasis: Development of a Pharmacokinetic model
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Os ácidos biliares (BA) são parte integrante do fluxo biliar e têm um papel importante na absorção intestinal. Quando a homeostase deste fluxo sofre alterações, podem surgir variadas consequências, incluindo a colestase. Sendo os fármacos uma das causas possíveis para esta patologia, estes podem gerar consequências ao nível do fígado chamadas de DILI (lesão hepática induzida por fármacos). Este é um tópico que tem sido alvo de muitos estudos e muito correlacionado com a inibição do BSEP. Quando um fármaco inibe este transportador, os BA não sofrem passagem para o canalículo biliar, havendo uma acumulação dentro do hepatócito. Está provado que a inibição farmacológica do BSEP é uma causa da colestase, sendo, no entanto, desconhecida a concentração de fármaco necessária para tal. Este trabalho foca-se nessa mesma questão, recorrendo a um modelo farmacocinético usando o programa Berkeley Madonna – Modeling and Analysis of Dynamic Systems Software. Este trabalho está integrado no projecto ASAT (Garantia de Segurança sem testes Animais), pelo que dados humanos tornam-se uma ferramenta essencial, sendo, porém, difícieis de obter. Alguns pressupostos ao nível do transporte passivo, taxa de síntese e de absorção de BA ao nível do hepatócito foram feitos neste modelo. Apenas a inibição competitiva foi tida em conta, simulando diferentes características farmacinéticas do fármaco em estudo, tais como o Km (Constante de Michaelis) e a concentração. Tendo em conta estas variáveis, a percentagem de inibição do BSEP é diferente para diferentes fármacos inibidores. Outra conclusão deste projecto é que o padrão de BA afectados pela inibiçao do BSEP torna-se diferente de acordo com esse mesmo grau de inibição. É ainda possível sugerir que outros transportadores poderão ser tão importantos quanto o BSEP para o effluxo de BA e consecutivamente para o aparecimento de colestase quando bloquados, tais como o MRP2 e o OSTαβ.
BA (Bile acids) generate bile flow and have an important role on intestinal absorption. When homeostasis of this flow is changed it can lead to different kind of consequences and diseases, including cholestasis. It can be consequence of pregnancy, stone in bile duct or drugs. Last one generates consequences to liver that can be called DILI (drug induced liver injury). It is a topic that has been studied and very correlated to BSEP inhibition. When a drug blocks this transporter, BA are not exported to bile canaliculi and it leads to their accumulation inside hepatocyte. Drug inhibition of BSEP is proved as a reason to cholestasis, however, it is not known which drug concentration leads to this consequence. This work is focused on that question, using a pharmacokinetic model through Berkeley Madonna – Modeling and Analysis of Dynamic Systems Software. As it is within ASAT Project (Assuring Safety without Animal Testing), human data became an important pool and also very difficult to find. For this pharmacokinetic model some assumptions were made, including for Passive transport, synthesis rate and uptake of BA to hepatocyte. On this study, only competitive inhibition was run in the model, using different drug characteristics, as Km (Michaelis Constant) and drug concentration. Taking into account those variables, the percentage of inhibition of BSEP is different for different used drugs. Other conclusion is that pattern of BA affected by BSEP inhibition becomes different according to inhibition degree. Also, according to this work, it may be suggested that other transporters can be as important as BSEP for efflux of BA and hence for cholestasis when blocked, as MRP2 and OSTαβ.
BA (Bile acids) generate bile flow and have an important role on intestinal absorption. When homeostasis of this flow is changed it can lead to different kind of consequences and diseases, including cholestasis. It can be consequence of pregnancy, stone in bile duct or drugs. Last one generates consequences to liver that can be called DILI (drug induced liver injury). It is a topic that has been studied and very correlated to BSEP inhibition. When a drug blocks this transporter, BA are not exported to bile canaliculi and it leads to their accumulation inside hepatocyte. Drug inhibition of BSEP is proved as a reason to cholestasis, however, it is not known which drug concentration leads to this consequence. This work is focused on that question, using a pharmacokinetic model through Berkeley Madonna – Modeling and Analysis of Dynamic Systems Software. As it is within ASAT Project (Assuring Safety without Animal Testing), human data became an important pool and also very difficult to find. For this pharmacokinetic model some assumptions were made, including for Passive transport, synthesis rate and uptake of BA to hepatocyte. On this study, only competitive inhibition was run in the model, using different drug characteristics, as Km (Michaelis Constant) and drug concentration. Taking into account those variables, the percentage of inhibition of BSEP is different for different used drugs. Other conclusion is that pattern of BA affected by BSEP inhibition becomes different according to inhibition degree. Also, according to this work, it may be suggested that other transporters can be as important as BSEP for efflux of BA and hence for cholestasis when blocked, as MRP2 and OSTαβ.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2016
Palavras-chave
Cholestasis BSEP Bile acids Inhibition Pharmacokinetic model Mestrado Integrado - 2016