Concentração dos metabólitos da Azatioprina e sua relação com os aspectos terapêuticos da Doença Inflamatória Intestinal

• Autor(a) principal: Duarte, Joselmo Willamys [UNIFESP]
• Data de Publicação: 2019
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Repositório Institucional da UNIFESP
• Texto Completo: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=8471443; https://repositorio.unifesp.br/handle/11600/59530
• topic: Inflammatory Bowel Disease; Clinical Pharmacological Management; Azathioprine; Concentration Of Metabolites; Therapeutic Aspects; Doença Inflamatória Intestinal; Manejo Clínico Farmacológico; Azatioprina; Concentração De Metabólitos; Aspectos Terapêuticos

Azathioprine (AZA) is one of the most commonly used immunosuppressants in the treatment of Intestinal Inflammatory Disease (IBD); however, its use can have several undesirable effects. In this context, the quantification of its active metabolites can provide important information in an individualized and accurate manner, making the treatment safer and more effective. However, there are doubts regarding the ideal levels of metabolites that may be associated with clinical, endoscopic and laboratory findings to indicate the therapeutic response of AZA, when it is used concomitantly with other drugs in the treatment of IBD. AIM: identify the concentrations of AZA metabolites, according to the prescribed therapeutic regimen, in a group of patients with IBD, and correlate them with the clinical, endoscopic and laboratory response for the improvement of therapeutic management. METHODS: 79 volunteers participated in this study [Crohn Disease(CD)=41 (51.9%); Ulcerative Colitis(UC)=38 (48.1%)], in which were carried out: quantitative analysis of metabolites through High-Performance Liquid Chromatography-UV (HPLC-UV); molecular analysis through Polymerase Chain Reaction/Restriction Fragment Length Polymorphism (PCR/RFLP); kinetics of the enzymes Aspartate aminotransferase (ASP) and Alanine aminotransferase (ALT); hematological analyzes by electrical impedance and light scattering; turbidimetric analysis of Fecal Calprotectin (FC), as well as serum C-reactive protein (CRP); and analysis of clinical and endoscopic characteristics of volunteers. RESULTS: volunteers with IBD came from the outpatient clinic for inflammatory bowel disease of the Gastroenterology Discipline of UNIFESP/EPM, the Outpatient Clinic for Inflammatory Bowel Diseases of Hospital Heliópolis and the Gastroenterology Clinic of Santa Casa de São Paulo. The doses received by the volunteers are poor predictors of the organic concentrations of the metabolites (p=0,798 and p=0,298), a significant difference between the average concentration of 6-TGN and 6-MMPr metabolites of the groups studied was found (p=0.001; p=0.006, respectively). The following heterozygous profile for the polymorphic variants studied has been detected: TPMT*2 [3(3,8%)], TPMT*3A [2(2,5%)], TPMT*3B [6(7,6%)] e TPMT*3C [3(3,8%)], these were weak predictors for 6-TGN concentration (p=0,560) and 6-MMPr concentration (p=0,753). The hepatic and hematological markers were not affected by the metabolites concentration, and 6-TGN has shown to be a weak predictor of the clinical [DC(p=0,647); RCUI(p=0,761)], endoscopic [DC(p=0,679); RCUI(p=0,874)] and laboratory [CF(p=0,292); CRP (p=0,954)] of AZA response in IBD (OR=0,9; IC95%=0,9–1,0). CONCLUSIONS: we conclude that at doses administered, they do not correlate with the organic concentrations of the metabolites. We identified levels of 6-TGN and 6-MMPr concentrations in each group with significant differences and influenced by the prescribed therapeutic regimens. These concentrations were not interfered with by the detected gene polymorphisms and were shown to be safe in relation to hepatic and hematological adversity. In our study, intraerythrocyte levels of metabolite 6-TGN were not predictors and did not correlate significantly by evaluating the clinical, endoscopic or laboratory response of pharmacotherapy by AZA in IBD.