Pharmacokinetics of Hydroxymethylnitrofurazone and Its Parent Drug Nitrofurazone in Rabbits

Abstract

The prodrug hydroximethylnitrofurazone (NFOH) presents antichagasic activity with greatly reduced toxicity compared to its drug matrix nitrofurazone (NF). Besides these new characteristics, the prodrug was more active against the parasite T. cruzi amastigotes. These advantages make the prodrug a possible therapeutic alternative for the treatment of both acute and the chronic phase of Chagas disease. However, the knowledge of pharmacokinetic profile is crucial to evaluate the feasibility of a new drug. In this study, our objective was to evaluate the in vivo formation of NF from the NFOH single administration and to evaluate its pharmacokinetic profile and compared it to NF administration. A bioanalytical method to determine the NF and NFOH by LCMS/MS was developed and validated to perform these investigations. Male albino rabbits (n=15) received NF intravenously and orally in doses of 6.35 and 63.5 mg / kg respectively, and NFOH, 80.5 mg / kg orally. The serial blood samples were processed and analyzed by mass spectrometry. The system operated in positive and negative modes for the analites determination, under elution of the mobile phase 50:50 water: methanol. The administration of NFOH allowed the calculation of pharmacokinetic parameters for the prodrug, and the NF obtained from NFOH administration. Using the pharmacokinetic profile obtained from the NF i.v. administration, the oral bioavailability of NF from the administered prodrug was obtained (60.1%) and, as a key parameter in a prodrug administration, should be considered in future studies. The i.v. and oral administrations of NF differ in the constant of elimination (0.04 vs 0.002) and elimination half-life (17.32 min vs 276.09 min) due to the low solubility of the drug that hinders the formation of molecular dispersions in the digestory tract. Still, there was observed no statistical differences were observed between the pharmacokinetic parameters of orally administered NF and NF obtained from NFOH. The calculated area under the curve (AUC 0-∞) showed that the exposure to the parental drug was fairly the same (844.79 vs 566.44) for NF and NF obtained from the prodrug administration. The tendency to higher NF's mean residence time (MRT) as observed in the prodrug administration (956.1 min vs 496.3 min) guarantees longer time for the action of the drug and it allows the expansion of the administration intervals. These findings, added with the beneficial characteristics of the prodrug encourage new efficacy tests towards the clinical use of NFOH.

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

“…However, NFOH produces fewer side effects, is less genotoxic, inhibits parasite replication by a different downstream mechanism, and as shown here, is considerably more active against the infectious trypomastigote form of the parasite. The reduced toxicity of NFOH, curative activity and potential for flexibility in terms of dosing regimens, also identifies it as an attractive partner for other anti-chagasic candidates in combination therapy [15,24,25,[27][28][29]40,42].…”

“…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].…”

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.…”

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

“…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.…”