Farmacocinética pré-clínica e cardiotoxicidade da doxorrubicina veiculada por sistema microemulsionado
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Data
2011-05-02
Autores
Assumpção, Juliana Uruguay Corrêa Vidigal [UNESP]
Título da Revista
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Neste estudo investigou-se o perfil farmacocinético da DOX administrada na forma de microemulsão lipídica, em dose única i.v (6 mg/kg), a ratos Wistar (n=12; 250 g) e comparou-se ao perfil farmacocinético da doxorrubicina administrada na forma de cloridrato em solução aquosa. Ainda, avaliou-se a atividade da CKMb nos dois grupos de animais antes e após a administração das formulações com o objetivo de evidenciar a cardiotoxicidade do produto. Para a avaliação do perfil farmacocinético foram colhidas amostras seriadas de sangue (0 – 16 h) através de cânulas previamente implantadas na veia femoral, e para a avaliação da atividade de CKMb foram colhidas amostras de sangue nos tempos zero, 1 h e 12 h após a administração das formulações. Para a determinação da doxorrubicina em amostras de sangue e nas formulações, desenvolveu- se e validou-se um método analítico por HPLC com detecção por fluorescência (exc= 480 nm; em= 560 nm), empregando-se coluna Xterra (C18, 5 µm, 3,9 x 150 mm) e fase móvel composta por 25% de acetonitrila e 75% de água na presença de ácido fórmico (0,1%) e de solução de amônia 25% (0,1%), pH 3,0 , com fluxo de 0,8 mL/min, em modo gradiente. Para as determinações da atividade da CKMb utilizou-se o kit labtest. O método analítico desenvolvido demonstrou limites de confiança adequados para a sua aplicação na determinação da DOX em formulações e em amostras de plasma para a avaliação do seu perfil farmacocinético. Os parâmetros farmacocinéticos que apresentaram diferenças estatisticamente significativas (p<0,05, Mann-Whitney) entre a microemulsão e solução aquosa, apresentados como média (IC 95), foram respectivamente: Vd (L/kg) = 38,23 (24,94 – 51,50) vs 68,85 (55,69 – 82,00); tss (h) = 45,33 ( 39,45 – 58,20) vs 33,23 ( 27,7 – 38,75); β(h-1 )= 0,0014 (0,00072 – 0,00208) vs 0,00078...
The present study investigated the DOX pharmacokinetic profile when administered as a lipid microemulsion in a single dose (6 mg/kg, IV) to Wistar rats (n=12; 250g) and compared it to the pharmacokinetic profile of doxorubicin administered as hydrochloride in aqueous solution. With the purpose of demonstrating the cardiotoxicity of the product it also evaluated the CKMB activity in both animal groups before and after administration of the formulations. Serial blood samples were obtained (0 – 16h) through cannulas previously implanted into the femoral vein to evaluate the pharmacokinetic profile. To evaluate the CKMB activity, blood samples were collected after the formulation was administered at times zero, 1h and 12h. An analytical method by HPLC with fluorescence detection (exc= 480 nm; em= 560 nm) was developed and validated for the determination of doxorubicin in blood samples and in the formulations. The column used as stationary phase was Xterra (C18, 5 µm, 3.9 x 150 mm) and the mobile phase was composed of 25% of acetonitrile and 75% of water in presence of formic acid (0.1%) and ammonia solution 25% (0.1%), pH 3.0 at a flow rate of 0.8 mL/min, gradient mode. The developed method demonstrated appropriate safety limits to its use in determining doxorubicin in formulations and in plasma samples, and therefore to evaluate the DOX pharmacokinetic profile. For the determination of CKMB activity it was used the Labtest. The pharmacokinetic parameters that showed statistically significant differences (p<0.05, Mann-Whitney) between the microemulsion and the aqueous solution, presented as medians (IC 95), were respectively: Vd (L/kg) = 38.23 (24.94 – 51.50) vs 68.85 (55.69 – 82.00); tss (h) = 45.33 (39.45 – 58.20) vs 33.23 ( 27.70 – 38.75); β(h-1 )= 0.0014 (0.00072 – 0.00208) vs 0.00078 ( 0.0004386 – 0.001076) and t1/2 (h) = 9.24 (5.31 – 13.17) vs 16.51 ... (Complete abstract click electronic access below)
The present study investigated the DOX pharmacokinetic profile when administered as a lipid microemulsion in a single dose (6 mg/kg, IV) to Wistar rats (n=12; 250g) and compared it to the pharmacokinetic profile of doxorubicin administered as hydrochloride in aqueous solution. With the purpose of demonstrating the cardiotoxicity of the product it also evaluated the CKMB activity in both animal groups before and after administration of the formulations. Serial blood samples were obtained (0 – 16h) through cannulas previously implanted into the femoral vein to evaluate the pharmacokinetic profile. To evaluate the CKMB activity, blood samples were collected after the formulation was administered at times zero, 1h and 12h. An analytical method by HPLC with fluorescence detection (exc= 480 nm; em= 560 nm) was developed and validated for the determination of doxorubicin in blood samples and in the formulations. The column used as stationary phase was Xterra (C18, 5 µm, 3.9 x 150 mm) and the mobile phase was composed of 25% of acetonitrile and 75% of water in presence of formic acid (0.1%) and ammonia solution 25% (0.1%), pH 3.0 at a flow rate of 0.8 mL/min, gradient mode. The developed method demonstrated appropriate safety limits to its use in determining doxorubicin in formulations and in plasma samples, and therefore to evaluate the DOX pharmacokinetic profile. For the determination of CKMB activity it was used the Labtest. The pharmacokinetic parameters that showed statistically significant differences (p<0.05, Mann-Whitney) between the microemulsion and the aqueous solution, presented as medians (IC 95), were respectively: Vd (L/kg) = 38.23 (24.94 – 51.50) vs 68.85 (55.69 – 82.00); tss (h) = 45.33 (39.45 – 58.20) vs 33.23 ( 27.70 – 38.75); β(h-1 )= 0.0014 (0.00072 – 0.00208) vs 0.00078 ( 0.0004386 – 0.001076) and t1/2 (h) = 9.24 (5.31 – 13.17) vs 16.51 ... (Complete abstract click electronic access below)
Descrição
Palavras-chave
Doxorrubicina, Farmacocinetica, Doxorubicin, Microemulsion, Pharmacokinetics, Cardiotoxicity
Como citar
ASSUMPÇÃO, Juliana Uruguay Corrêa Vidigal. Farmacocinética pré-clínica e cardiotoxicidade da doxorrubicina veiculada por sistema microemulsionado. 2011. 94 f. Dissertação (mestrado) - Universidade Estadual Paulista, Faculdade de Ciências Farmacêuticas, 2011.