Síntese, atividade antibacteriana e farmacocinética pré-clínica de pró-fármaco do etambutol com potencial terapêutico para meningite tuberculosa
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Data
2010-06-28
Autores
Pinto, Leonardo Santos Ribeiro [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
O etambutol é preconizado no tratamento da meningite tuberculosa sempre associado a outro fármaco tuberculostático. Mas, embora útil quanto à sua ação, o fármaco não atravessa satisfatoriamente a barreira hematoencefálica. Desta forma, este trabalho propôs a síntese e caracterização estrutural de um pró-fármaco de etambutol (DEREMB) para melhorar a sua penetração no SNC; assim como a realização de estudos de atividade antibacteriana, estabilidade in vitro e ex vivo e, ainda, investigação da disposição cinética do composto; comparando-a com a do etambutol, em ratos wistar (machos, n=20, peso~200g) tratados com dose única via endovenosa (25 mg/kg) e via gavagem (100 mg/kg). A modificação molecular do etambutol alterou a lipossolubilidade do composto, expressa pelo log P, aumentando a possibilidade de penetração no sistema nervoso central, e o aumento da permeabilidade celular, haja vista que o DEREMB apresentou atividade, ainda que menor contra o M. tuberculosis quando comparada ao fármaco matriz. Os resultados obtidos nos ensaios de hidrólise em diferentes pHs (1,2 e 7,4) e na submissão à ação de enzimas plasmáticas permitem observar estabilidade do produto no período de 24 horas. Os parâmetros farmacocinéticos expressos através das médias (IC95%) foram: DEREMB (endovenoso): Cmax (ug/mL)= 10,4; AUC 0-t(ug/mL.min)=252,7; AUC 0-µ(ug/mL.min)= 294,3; Vd (L/kg)=4,3 ; CIT (mL/min/kg)=86,4 ; t ½ (min) =43,1;b (min-1)= 0,021. As baixas concentrações plasmáticas obtidas na administração oral do DEREMB não permitiram o calculo do parâmetros farmacocinéticos por esta via. Apenas os parâmetros Cmax e Vd do DEREMB não apresentaram diferenças estatísticas significativas quando comparados ao etambutol
Ethambutol is a tuberculostatic drug indicated for tuberculous meningitis treatment. But, although useful as for its action, the drug does not cross the blood-brain barrier satisfactorily; certainly reducing its effectiveness in the treatment of the tuberculous meningitis. In this way, this work proposed the synthesis and structural characterization of a prodrug of ethambutol (DEREMB) to improve its penetration in SNC; as well as the accomplishment of studies of antibacterial activity, in vitro and ex vivo stability studies and, still, the investigation of the kinetic disposition of the compound comparing it with the pharmacokinetic profile of ethambutol, in rats wistar (males, n=20, weigth~200g) treated with single iv dose(25 mg/kg) and by gavage (100 mg/kg). The produced prodrug presents a greater lipophilicity – expressed by logp - what could increase its permeation through the blood-brain barrier and its cellular permeability, once the DEREMB presented antimycobacterial activity, although smaller when compared to ethambutol. The in vitro and ex vivo (plasma) hydrolysis studies demonstrates that ethambutol derivative is stable and is not converted to ethambutol in the different pHs which occur in digestory tract or by plasmatic enzymes.. The pharmacokinetic parameters of DEREMB (iv) were: Cmax (ug/mL) = 10,4; AUC 0-t(ug/mL.min)=252,7; AUC 0 - (ug/mL.min) = 294,3; Vd (L/kg)=4,3; CIT (mL/min/kg)=86,4; t ½ (min) =43,1; (min-1) = 0,021. The low plasmatic concentrations obtained in the oral administration of DEREMB did not allow to calculate its pharmacokinetic parameters. Only Cmax and Vd parameters of DEREMB did not present significant statistical differences when compared to ethambutol
Ethambutol is a tuberculostatic drug indicated for tuberculous meningitis treatment. But, although useful as for its action, the drug does not cross the blood-brain barrier satisfactorily; certainly reducing its effectiveness in the treatment of the tuberculous meningitis. In this way, this work proposed the synthesis and structural characterization of a prodrug of ethambutol (DEREMB) to improve its penetration in SNC; as well as the accomplishment of studies of antibacterial activity, in vitro and ex vivo stability studies and, still, the investigation of the kinetic disposition of the compound comparing it with the pharmacokinetic profile of ethambutol, in rats wistar (males, n=20, weigth~200g) treated with single iv dose(25 mg/kg) and by gavage (100 mg/kg). The produced prodrug presents a greater lipophilicity – expressed by logp - what could increase its permeation through the blood-brain barrier and its cellular permeability, once the DEREMB presented antimycobacterial activity, although smaller when compared to ethambutol. The in vitro and ex vivo (plasma) hydrolysis studies demonstrates that ethambutol derivative is stable and is not converted to ethambutol in the different pHs which occur in digestory tract or by plasmatic enzymes.. The pharmacokinetic parameters of DEREMB (iv) were: Cmax (ug/mL) = 10,4; AUC 0-t(ug/mL.min)=252,7; AUC 0 - (ug/mL.min) = 294,3; Vd (L/kg)=4,3; CIT (mL/min/kg)=86,4; t ½ (min) =43,1; (min-1) = 0,021. The low plasmatic concentrations obtained in the oral administration of DEREMB did not allow to calculate its pharmacokinetic parameters. Only Cmax and Vd parameters of DEREMB did not present significant statistical differences when compared to ethambutol
Descrição
Palavras-chave
Farmacocinetica, Meningite, Etambutol, Ethambutol
Como citar
PINTO, Leonardo Santos Ribeiro. Síntese, atividade antibacteriana e farmacocinética pré-clínica de pró-fármaco do etambutol com potencial terapêutico para meningite tuberculosa. 2010. 121 f. +. Dissertação (mestrado) - Universidade Estadual Paulista, Faculdade de Ciências Farmacêuticas, 2010.