Pharmacokinetics and Tissue Distribution of Benznidazole after Oral Administration in Mice

Abstract

Specific chemotherapy using benznidazole (BNZ) for Chagas disease during the chronic stage is controversial due to its limited efficacy and toxic effects. Although BNZ has been used to treat Chagas disease since the 1970s, few studies about the biodistribution of this drug exist. In this study, BNZ tissue biodistribution in a murine model and its pharmacokinetic profile in plasma were monitored. A bioanalytical high-performance liquid chromatography method with a UV detector (HPLC-UV) was developed and validated according to the European Medicines Agency for quantification of BNZ in organs and plasma samples prepared by liquidliquid extraction using ethyl acetate. The developed method was linear in the BNZ concentration, which ranged from 0.1 to 100.0 g/ml for plasma, spleen, brain, colon, heart, lung, and kidney and from 0.2 to 100.0 g/ml for liver. Validation assays demonstrated good stability for BNZ under all conditions evaluated. Pharmacokinetic parameters confirmed rapid, but low, absorption of BNZ after oral administration. Biodistribution assays demonstrated different maximum concentrations in organs and similar times to maximum concentration and mean residence times, with means of 40 min and 2.5 h, respectively. Therefore, the biodistribution of BNZ is extensive, reaching organs such as the heart and colon, which are the most relevant organs affected by Trypanosoma cruzi infection, and also the spleen, brain, liver, lungs, and kidneys. Simultaneous analyses of tissues and plasma indicated high BNZ metabolism in the liver. Our results suggest that low bioavailability, instead of inadequate biodistribution, could be responsible for therapeutic failure during the chronic phase of Chagas disease.

Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular Trypanosoma cruzi Amastigotes

“…Among Chagas patients, following cessation of benznidazole treatment, a subset of individuals reverted from PCR-negative status to having detectable parasite DNA, indicating parasite persistence in such cases ( 8 , 25 ). Several explanations have been proposed to account for this lack of sterilizing cure by benznidazole in humans, including inadequate biodistribution, low solubility, high levels of serum binding, and low bioavailability through extensive liver metabolism ( 51 – 54 ). On the basis of our current findings, it is conceivable that the flexibility of the T. cruzi amastigote may serve to protect tissue resident parasites from insufficient exposure to drug.…”

Experimental and Clinical Treatment of Chagas Disease: A Review

“…It is likely that ring cleavage also occurs. 177 To the best of our knowledge, the more complete study about BZ biodistribution was performed in mice by Perin et al, 180 which BZ concentration ranged from 0.1 to 100.0 μg/mL for plasma, spleen, brain, colon, heart, lung, and kidney and from 0.2 to 100.0 μg/mL for liver after oral administration of BZ. There were similar times to maximum concentration in organs, with means of 40 minutes.…”

Flavonoids as efficient scaffolds: Recent trends for malaria, leishmaniasis, Chagas disease, and dengue

“…To recap, some reported flavonoids such as naringenin ( T 1/2: 2.31 hr), vitexin‐4″‐ O ‐glucoside ( T 1/2: 2.53 hr), and vitexin‐2″‐ O ‐rhamnoside ( T 1/2: 2.32 hr) showed elimination half‐lives comparable with those of standard antiparasitic drugs such as nifurtimox ( T 1/2: 2.95 hr; Paulos et al, ); benznidazole ( T 1/2: 2.03 hr; Perin et al, ); and artemisinin ( T 1/2: 2 to 5 hr; Woodrow, Haynes, & Krishna, ), among others. However, lead optimization through a prodrug design (that aims at enhancing drug permeation by increasing lipophilicity or by improving aqueous solubility and bioavailability) approach would be beneficial to improve the pharmacokinetic properties of the in vitro active flavonoids.…”