Pharmacokinetics of Hydroxymethylnitrofurazone, a Promising New Prodrug for Chagas' Disease Treatment

Abstract

dHydroxymethylnitrofurazone (NFOH) is a trypanocidal prodrug of nitrofurazone (NF), devoid of mutagenic toxicity. The purpose of this work was to study the chemical conversion of NFOH into NF in sodium acetate buffer (pH 1.2 and 7.4) and in human plasma and to determine preclinical pharmacokinetic parameters in rats. At pH 1.2, the NFOH was totally transformed into NF, the parent drug, after 48 h, while at pH 7.4, after the same period, the hydrolysis rate was 20%. In human plasma, 50% of NFOH was hydrolyzed after 24 h. In the investigation of kinetic disposition, the concentration of drug in serum versus time curve was used to calculate the pharmacokinetic parameters after a single-dose regimen. NFOH showed a time to maximum concentration of drug in serum (T max ) as 1 h, suggesting faster absorption than NF (4 h). The most important results observed were the volume of distribution (V) of NFOH through the tissues, which showed a rate that is 20-fold higher (337.5 liters/kg of body weight) than that of NF (17.64 liters/kg), and the concentration of NF obtained by in vivo metabolism of NFOH, which was about four times lower (maximum concentration of drug in serum [C max] ‫؍‬ 0.83 g/ml; area under the concentration-time curve from 0 to 12 h [AUC 0 -12] ‫؍‬ 5.683 g/ml · h) than observed for administered NF (C max ‫؍‬ 2.78 g/ml; AUC 0 -12 ‫؍‬ 54.49 g/ml · h). These findings can explain the superior activity and lower toxicity of the prodrug NFOH in relation to its parent drug and confirm NFOH as a promising anti-Chagas' disease drug candidate.

Hepatotoxicity in Mice of a Novel Anti-parasite Drug Candidate Hydroxymethylnitrofurazone: A Comparison with Benznidazole

“…Due to high toxicity concerns, BZL and NFX are not always recommended for treatment of immuno-suppressed patients [38] . In this scenario, NFOH has emerged as a promising compound for its anti- T. cruzi activity, both in vitro and in vivo , and its favorable pharmacological properties [39] , [40] . NFOH, derived from hydroxymethyl substitution at the primary amide of nitrofurazone [15] , also has a higher solubility in water than does NF and BZL, which likely would facilitate its oral administration.…”

Image-Based In Vitro Screening Reveals the Trypanostatic Activity of Hydroxymethylnitrofurazone against Trypanosoma cruzi

“…Hydroxymethylnitrofurazone (NFOH-a nitrofurazone derivative) is non-mutagenic in the Ames test [24], non-genotoxic in micronuclei [25], and pharmacokinetic studies in rats [26] and rabbits [27] have shown an increased distribution volume compared to its parent compound nitrofurazone. Additionally, when NFOH toxicity was evaluated after 21 and 60 days treatment, there was reduced hepatic inflammation compared to BZN, and no changes in hepatic enzymes such as aspartate aminotransferase and alanine aminotransferase [28,29].…”

Hydroxymethylnitrofurazone treatment in indeterminate form of chronic Chagas disease: Reduced intensity of tissue parasitism and inflammation—A histopathological study

“…The NFOH was four times less mutagenic than NF through the AMES test, and it did not show in vivo genotoxicity . In addition, the pharmacokinetic study has shown an increased bioavailability that is around 20 times more in rats and 10% in rabbits …”

“…15 In addition, the pharmacokinetic study has shown an increased bioavailability that is around 20 times more in rats and 10% in rabbits. 16,17 The improved activity of NFOH in comparison with NF can be explained by the nucleophilic attack of Cys25 residue present in the enzyme cruzain of T. cruzi to the carbonyl group present in the semicarbazone subunit of NFOH. At the same concentration, NF inhibited 30% of cruzain, while for NFOH, a value of 60% was recorded.…”