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

Suzana Marques de Jesus; Leonardo Pinto; Fernanda de Lima Moreira; Glauco Henrique Balthazar Nardotto; Rodrigo Cristofoletti; Luísa Perin; Kátia da Silva Fonseca; Pauliana Barbêdo; Lorena Cera Bandeira; Paula Melo de Abreu Vieira; Claudia Martins Carneiro

doi:10.1128/AAC.01383-20

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

Antimicrob Agents Chemother. 2021 Jan 20;65(2):e01383-20. doi: 10.1128/AAC.01383-20. Print 2021 Jan 20.

Affiliations

¹ Laboratory of Immunopathology, Nucleus of Biological Sciences Research, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
² Laboratory of Immunopathology, Nucleus of Biological Sciences Research, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil leonardopinto84@gmail.com.
³ 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.
⁴ Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA.
⁵ 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.
⁶ Department of Clinical Analysis, School of Pharmacy, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil.

^# Contributed equally.

Abstract

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.

Keywords: Chagas disease; Trypanosoma cruzi; benznidazole; pharmacokinetics; preclinical drug studies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chagas Disease* / drug therapy
Female
Humans
Mice
Nitroimidazoles* / therapeutic use
Tissue Distribution
Trypanocidal Agents* / therapeutic use
Trypanosoma cruzi*

Substances

Nitroimidazoles
Trypanocidal Agents
benzonidazole