Pharmacokinetics of hydroxymethylnitrofurazone, a promising new prodrug for Chagas' disease treatment

Abstract

Hydroxymethylnitrofurazone (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 (Tmax) 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 [Cmax] = 0.83 μg/ml; area under the concentration-time curve from 0 to 12 h [AUC0-12] = 5.683 μg/ml · h) than observed for administered NF (Cmax = 2.78 μg/ml; AUC0-12 = 54.49 μg/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.

Fig 1

Structures of nitrofurazone (NF) (left) and hydroxymethylnitrofurazone (NFOH) (right).

Fig 2

Conversion profile of NFOH to NF* in sodium acetate buffer (pH 1.2) at 37°C.

Fig 3

Conversion profile of NFOH to NF* in sodium acetate buffer (pH 7.4) at 37°C.

Fig 4

Conversion of NFOH to NF* in human plasma samples (pH 7.4) at 37°C.

Fig 5

Time-dependent concentrations of NFOH and NF* in plasma, obtained after NFOH administration to male Wistar rats. Data are expressed as means and standard errors of the means (SEM) (n = 50).

Fig 6

Time-dependent concentration of NF in plasma obtained after NF administration to male Wistar rats. Data are expressed as means and SEM (n = 50).

Fig 7

Comparative study of the hydrolysis of NFOH after reaching C_max in human serum and in vivo.