Pharmacokinetics, biodistribution, and in vivo toxicity of 7-nitroindazole loaded in pegylated and non-pegylated nanoemulsions in rats

Abstract

Sepsis is a life-threatening condition caused by a dysregulated host response to infection. The development of sepsis is associated with excessive nitric oxide (NO) production, which plays an important role in controlling vascular homeostasis. 7-nitroindazole (7-NI) is a selective inhibitor of neuronal nitric oxide synthase (NOS-1) with potential application for treating NO imbalance conditions. However, 7-NI exhibits a low aqueous solubility and a short plasma half-life. To circumvent these biopharmaceutical limitations, pegylated (NEPEG_7NI) and non-pegylated nanoemulsions (NENPEG_7NI) containing 7-NI were developed. This study evaluates the pharmacokinetic profiles and toxicological properties of 7-NI loaded into the nanoemulsions. After a single intravenous administration of the free drug and the nanoemulsions at a dose of 10 mg.kg^-1 in Wistar rats, 7-NI was widely distributed in the organs. The pharmacokinetic parameters of C_max, t_1/2, and AUC_0-t were significantly increased after administration of the NEPEG_7NI, compared to both free 7-NI and NENPEG_7NI (p < 0.05). No observable adverse effects were observed after administering the free 7-NI, NEPEG_7NI, or NENPEG_7NI in the animals after a single dose of up to 3.0 mg.kg^-1. The results indicated that 7-NI-loaded nanoemulsions are safe, constituting a promising approach to treating sepsis.

Keywords: 7-nitroindazole; in vivo toxicity; nanoemulsions; pharmacokinetics; sepsis.