Determinantes Farmacogenômicos do Diabetes Mellitus Pós-Transplante Hepático: Uma Revisão Sistemática e Análise Farmacogenômica In Silico
Palavras-chave:
Tacrolimo, Farmacogenética, Transplante de Fígado, Diabetes MellitusResumo
O tacrolimo permanece central no transplante hepático, porém seu índice terapêutico estreito e sua variabilidade farmacocinética estão associados ao risco aumentado de diabetes mellitus pós-transplante (DMPT). Embora polimorfismos em enzimas metabolizadoras modulem a exposição ao fármaco e o risco diabetogênico, essa relação não foi sistematicamente integrada por meio de abordagens farmacogenômicas direcionadas. Objetivou-se aqui avaliar sistematicamente variantes genéticas em genes metabolizadores de tacrolimo e suas associações com DMPT por meio de análise farmacogenômica in silico integrada. Foi realizada uma análise in silico integrando dados de repositórios públicos (PharmGKB), literatura curada e anotações funcionais de variantes genéticas. Modelos de aprendizado de máquina foram desenvolvidos utilizando-se dados sintéticos gerados de tamanhos de efeito derivados da literatura para demonstrar viabilidade de prova de conceito. Priorizamos genes (CYP3A5, CYP3A4, ABCB1) com base nos níveis de evidência do PharmGKB, impacto funcional e associações clínicas com exposição ao tacrolimo e risco de DMPT, incorporando informações genotípicas, dosagem do fármaco e desfechos metabólicos. O alelo CYP3A5*1 emergiu como determinante-chave, consistentemente requerendo doses de tacrolimo 1,5 a 2,8 vezes maiores e conferindo risco significativamente elevado de DMPT comparado a não expressores, efeito mediado pela exposição cumulativa ao fármaco. Na revisão sistemática e modelagem sintética, portadores de alelos funcionais CYP3A5 com genótipos expressores exibiram risco significativamente aumentado de DMPT em relação a não expressores, demonstrando clara relação dose–exposição–toxicidade. Em contraste, CYP3A4 e ABCB1 apresentaram apenas evidência sugestiva, porém heterogênea, de associação. Este estudo farmacogenômico in silico demonstra associação clinicamente significativa entre variabilidade genética no metabolismo do tacrolimo e o desenvolvimento de DMPT após transplante hepático. Esses achados sustentam estratégias orientadas por genótipo para otimizar a terapia imunossupressora e avançar a medicina de precisão no cuidado pós-transplante.
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Copyright (c) 2026 Luis Jesuino de Oliveira Andrade, Raymundo Paraná , Gabriela Correia Matos de Oliveira , Alcina Maria Vinhaes Bittencourt , Osmário Jorge de Mattos Salles , Luís Matos de Oliveira
Este trabalho está licenciado sob uma licença Creative Commons Attribution 4.0 International License.
