Pharmacokinetics of Benznidazole in Experimental Chronic Chagas Disease Using the Swiss Mouse-Berenice-78 Trypanosoma cruzi Strain Model.

Autor: de Jesus SM; Laboratory of Immunopathology, Nucleus of Biological Sciences Research, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil., Pinto L; Laboratory of Immunopathology, Nucleus of Biological Sciences Research, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil leonardopinto84@gmail.com., Moreira FL; Laboratory of Clinical Pharmacokinetics, Department of Clinical, Toxicological, and Bromatological Analyses, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Nardotto GHB; Laboratory of Clinical Pharmacokinetics, Department of Clinical, Toxicological, and Bromatological Analyses, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Cristofoletti R; Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA., Perin L; Laboratory of Immunopathology, Nucleus of Biological Sciences Research, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil., Fonseca KDS; Laboratory of Immunopathology, Nucleus of Biological Sciences Research, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil., Barbêdo P; Laboratory of Immunopathology, Nucleus of Biological Sciences Research, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil., Bandeira LC; Laboratory of Immunopathology, Nucleus of Biological Sciences Research, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil., Vieira PMA; Laboratory of Immunopathology, Nucleus of Biological Sciences Research, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil.; Laboratory of Morphopathology, Department of Biological Sciences, Nucleus of Biological Sciences Research, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil., Carneiro CM; Laboratory of Immunopathology, Nucleus of Biological Sciences Research, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil.; Department of Clinical Analysis, School of Pharmacy, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
Jazyk: angličtina
Zdroj: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2021 Jan 20; Vol. 65 (2). Date of Electronic Publication: 2021 Jan 20 (Print Publication: 2021).
DOI: 10.1128/AAC.01383-20
Abstrakt: 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 ( K a ) (3.92 versus 1.82 h -1 ), 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 ( T max ) (0.67 versus 1.17 h) and absorption half-life ( t 1/2 a ) (0.18 versus 0.38 h). Tissue exposure (area under the concentration-versus-time curve from 0 h to time t for tissue [AUC 0- t ,tissue ]) was longer and higher in the colon (8.15 versus 21.21 μg · h/g) and heart (5.72 versus 13.58 μg · h/g) of chronically infected mice. Chronic infection also increased the benznidazole tissue penetration ratios (AUC 0- t ,tissue /AUC 0- t ,serum ratios) of brain, colon, and heart by 1.6-, 3.25-, and 3-fold, respectively. The experimental chronic Chagas disease inflammation-mediated 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.
(Copyright © 2021 American Society for Microbiology.)
Databáze: MEDLINE
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