Browsing by Author "Nardotto, Glauco Henrique Balthazar"

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    Pharmacokinetics of Benznidazole in experimental chronic Chagas Disease using the Swiss mouse-Berenice-78 Trypanosoma cruzi strain model.
    (2021) Jesus, Suzana Marques de; Pinto, Leonardo Santos Ribeiro; Moreira, Fernanda de Lima; Nardotto, Glauco Henrique Balthazar; Cristofoletti, Rodrigo; Melo, Luísa Helena Perin de; Fonseca, Kátia da Silva; Barbêdo, Pauliana; Bandeira, Lorena Cera; Vieira, Paula Melo de Abreu; Carneiro, Cláudia Martins
    Chronic Chagas disease might have an impact on benznidazole pharmacokinetics with potential alterations in the therapeutic dosing regimen. This study aims to investigate the influence of chronic Trypanosoma cruzi infection on the pharmacokinetics and biodistribution of benznidazole in mice. Healthy (n= 40) and chronically T. cruzi (Berenice-78 strain)-infected (n= 40) Swiss female 10-month-old mice received a single oral dose of 100 mg/kg of body weight of benznidazole. Serial blood, heart, colon, and brain samples were collected up to 12 h after benznidazole administration. The serum and tissue samples were analyzed using a high-performance liquid chromatography instrument coupled to a diode array detector. Chronic infection by T. cruzi increased the values of the pharmacokinetic parameters absorption rate constant (Ka) (3.92 versus 1.82 h21 ), apparent volume of distribution (V/F) (0.089 versus 0.036 liters), and apparent clearance (CL/F) (0.030 versus 0.011 liters/h) and reduced the values of the time to the maximum concentration of drug in serum (Tmax) (0.67 versus 1.17 h) and absorption half-life (t1/2a) (0.18 versus 0.38 h). Tissue exposure (area under the concentration-versus-time curve from 0 h to time t for tissue [AUC0–t,tissue]) was longer and higher in the colon (8.15 versus 21.21mg · h/g) and heart (5.72 versus 13.58mg · h/g) of chronically infected mice. Chronic infection also increased the benznidazole tissue penetration ratios (AUC0–t,tissue/AUC0–t,serum ratios) of brain, colon, and heart by 1.6-, 3.25-, and 3-fold, respectively. The experimental chronic Chagas disease inflammationmediated changes in the regulation of membrane transporters probably influence the benznidazole pharmacokinetics and the extent of benznidazole exposure in tissues. These results advise for potential alterations in benznidazole pharmacokinetics in chronic Chagas disease patients with possibilities of changes in the standard dosing regimen.
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    Population pharmacokinetics and biodistribution of benznidazole in mice.
    (2020) Melo, Luísa Helena Perin de; Pinto, Leonardo Santos Ribeiro; Nardotto, Glauco Henrique Balthazar; Fonseca, Kátia da Silva; Paiva, Beatriz Oliveira; Mendes, Thaís Fernanda Rodrigues Bastos; Molina, Israel; Oliveira, Rodrigo Corrêa de; Vieira, Paula Melo de Abreu; Carneiro, Cláudia Martins
    Objectives: To evaluate the population pharmacokinetics of different benznidazole treatment regimens and the drug’s biodistribution in mice. Methods: Two hundred mice were divided into five groups according to benznidazole dosing regimens: (1) 100 mg/kg/day for 20 days; (2) 100 mg/kg/day for 40 days; (3) 200 mg/kg/day for 20 days; (4) 40 mg/kg/day for 20 days; or (5) 40 mg/kg/day for 40 days. The mice were euthanized and blood, heart, liver, colon and brain were collected. Samples were prepared by liquid-liquid extraction and analysed by HPLC-diode-array detection. The pharmacokinetic analysis of benznidazole was evaluated via non-linear mixed-effects modelling using the NONMEN program. Results: Our results demonstrate that mouse weight allometrically influences benznidazole clearance; the AUC curve and the highest plasma concentration are dose proportional; benznidazole does not influence its own metabolism; its tissue distribution is limited; and the standard treatment regimen for Chagas’ disease in mice (100 mg/kg/day for 20 days) is inadequate from a pharmacokinetic standpoint, as are the other regimens tested in this study (100 mg/kg/day for 40 days, 200 mg/kg/day for 20 days and 40 mg/kg/day for 20 or 40 days). Conclusions: Benznidazole reformulations that allow better tissue penetration and plasma and tissue exposure should be evaluated to enable higher cure rates in both animals and patients. The population pharmacokinetic model developed here can allow optimization of the dosing regimen of benznidazole to treat experimental Chagas’ disease. Determining appropriate treatment regimens in animals allows translation of these to clinical studies.