# Influence of Chagas Disease on the Pharmacokinetics of Benznidazole in the Dog Model

## TL;DR

This study shows that chronic Chagas disease in dogs changes how the drug benznidazole is processed in the body, possibly due to inflammation.

## Contribution

The study reveals that chronic T. cruzi infection alters benznidazole pharmacokinetics, likely through IL-6 mediated P-glycoprotein inhibition.

## Key findings

- Chronic infection increased benznidazole's Cmax, Css, and AUC0–12 compared to healthy and acute groups.
- Chronic infection decreased benznidazole's Vd/F and CL/F compared to healthy and acute groups.
- IL-6 levels were elevated about 7-fold during chronic infection.

## Abstract

The high variability in efficacy and safety of antichagasic
chemotherapy
involving benznidazole (BNZ) may be due to pharmacokinetic-related
factors. The study evaluated the impact of experimental acute and
chronic infections by the Berenice-78 strain of Trypanosoma
cruzi on the pharmacokinetics of BNZ in dogs. Twenty-seven
mongrel dogs were divided into the following groups: acute infection
state treated with BNZ, chronic infection state treated with BNZ,
acute and chronic positive controls (not treated with BNZ), and a
healthy group treated with BNZ. They were evaluated at (1) basal state,
(2) during infection without treatment, for cytokines panel (IL-6,
interferon γ (IFN-γ), IL-10 and tumor necrosis factor
α (TNF-α)) evaluation, and (3) during BNZ steady-state
levels at 10, 30, 40, and 60 days after start of treatment with oral
BNZ 3.5 mg/kg b.i.d. administration, in acute and chronic T. cruzi-infection, for BNZ pharmacokinetics and
cytokines panel evaluation, and (4) 30 days after BNZ treatment end
for cytokines evaluation. BNZ levels in serum samples were quantified
using a curve range of 0.1–100 μg/mL in plasma by high-performance
liquid chromatography with diode array detection (HPLC-DAD) analysis.
Pharmacokinetic parameters remained stable during treatment phases,
indicating no autoinduction or inhibition. Acute infection pharmacokinetics
resembled that of healthy controls. Chronic infection significantly
increased C
max, C
ss, and AUC0–12, while decreasing Vd/F and
CL/F compared to both healthy and acute groups. Notably, IL-6 levels
were elevated ∼7-fold during chronic infection. These data
suggest that chronic inflammatory status modulates BNZ disposition,
likely via IL-6 mediated P-glycoprotein inhibition. Understanding
these pharmacokinetic changes is critical for optimizing BNZ dosing
strategies in Chagas disease management.