Farmacocinética e farmacodinâmica de derivado ftalimídico planejado para o tratamento da anemia falciforme

• Ano de defesa: 2015
• Autor(a) principal: Campos, Michel Leandro de [UNESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Estadual Paulista (Unesp)
• Palavras-chave em Português: Anemia falciforme; Espectrometria de massa; Farmacocinética; Pharmacokinetics
• Link de acesso: http://hdl.handle.net/11449/134012

Sickle cell disease is a severe monogenic disorder, whose complications include the increase in the susceptibility to infections, acute splenic sequestration, aplastic crisis, acute thoracic syndrome, vaso-occlusive crisis, cerebrovascular disease, bone disease, priapism and leg ulcerations. The design, synthesis and evaluation of new compounds are necessary in order to renew the hopefulness of those affected by this disease, and the preclinical pharmacokinetic study, PK/PD study, metabolism study and safety evaluations, are an indispensable part of the development of these candidates as LAPDESF-SCD03. The preclinical pharmacokinetic and the TNF-α inhibition evaluation have been done using ultra performance liquid chromatography and immunoassay, respectively. The metabolite study has been made using Wistar rat hepatocytes and analyzed liquid chromatography coupled to high resolution mass spectrometry. The main results in the pharmacokinetic parameters were the short half-life (4.7 minutos) and the high clearance (172,5 mL/min.kg). In the oral administration, the MRT was ten-fold higher than the observed one in the iv administration, while the half-life was 30 minutes. In the PK/PD study, it was observed TNF-α reduction by both routes of administration, intravenous and oral. The metabolism study has addressed the formation of open ring metabolite, even though in the absence of the functional cells. Aftermath, the drug has shown activity and its pharmacokinetic was achieved, including the identification of a probable metabolite, which maybe can be pharmacologically active.