Work

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

Year: 2026

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide 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 AUC 0–12, 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.

Source: ACS Pharmacology & Translational Science

DOI: 10.1021/acsptsci.5c00571