Alterações farmacocinéticas de drogas pelo citocromo P450 na leishmaniose visceral humana

• Ano de defesa: 2014
• Autor(a) principal: Souza, Tânia Maria Vieira
• Orientador(a): Almeida, Roque Pacheco de
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Programa de Pós-Graduação: Pós-Graduação em Ciências da Saúde
• Palavras-chave em Português: Leishmaniose visceral; Farmacocinética; Citocromo P450
• Palavras-chave em Inglês: Cytochrome P450; Kala-azar; Pharmacokinetics
• Área do conhecimento CNPq: CNPQ::CIENCIAS DA SAUDE
• Link de acesso: https://ri.ufs.br/handle/riufs/3913

Studies in humans and laboratory animals have shown that inflammation and infectious processes are associated with changes in expression and activity of cytochrome P450 (CYP), which are responsible for the metabolism of most drugs in clinical use. In this context, the objectives of this work were: observe pharmacokinetic changes of CYP450 during human visceral leishmaniasis, describe the epidemiological, clinical and laboratory characteristics of patients with visceral leishmaniasis and evaluate the activity of the isoenzymes CYP3A4, CYP2C9 and CYP2C19 in patients with visceral leishmaniasis before and after treatment. This is a cross-sectional study, developed into an inpatient unit of a school hospital linked to the Federal University of Sergipe, reference in the diagnosis and treatment of visceral leishmaniasis in the state, which involved 24 patients. The study was conducted in four phases: before treatment, immediately after treatment, ninety and one hundred and eighty days after the end of treatment. In each phase, patients ingested the medication omeprazole (CYP2C19 substrate), losartan (CYP2C9 substrate) and midazolam (CYP3A4 substrate), which were used as evidence of the enzymes for which are substrates. Collecting blood samples (5 mL) of the patients before the administration of these drugs and 15, 30, 45 minutes and 1, 2, 3, 4, 5 and 6 hours after administration of those drugs. It was also collected all urine produced in 8 hours after the ingestion of drugs and separate a aliquot of 20 mL for analysis. Liquid chromatography coupled to mass spectrometry high efficiency (LC-MS) was used for the quantification of drugs and metabolites in the samples. The reason omeprazol/5-hidróxi-omeprazol plasma concentrations obtained 4 h after drug administration was used to evaluate the activity of CYP2C19, and the CYP2C9 enzyme activity was estimated by the ratio of concentrations losartano/E-3174 in urine collected 8h after administration of the drug. To estimate the activity of CYP3A4 was calculated the apparent clearance (CL / F) of midazolam. The results showed a prevalence of the disease in males and that most cases occurred in patients residing in urban areas. In relation to the clinical findings were present weight loss, fever, malaise and hepatomegaly in 100% of participants, and 50% were diagnosed between 90 and 180 days the onset of symptoms. On laboratory changes, anemia, leukopenia, thrombocytopenia, hypoalbuminemia, normal or slightly altered transaminases were found. As the enzymatic activity, the apparent clearance of midazolam found himself reduced during illness and increased after treatment; the metabolic ratio of omeprazole plasma concentration of 5-hydroxy-omeprazole and the ratio of the concentration urine losartano/E-3174 were increased during illness, and reduced after treatment, indicating a reduction in the activity of CYP3A4, 2C9 and 2C19 during LV and increase after treatment. The knowledge that occur changes on the activity of the cytochromes P450 and, consequently, on the pharmacokinetics of drugs during visceral leishmaniasis, may contribute to better understanding of the response to drugs during the disease.