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

• Published in: European journal of pharmaceutical sciences Vol. 194; p. 106695
• Main Authors: França, Angela Patricia, Silva, Thais Alves, Schulz, Daniela, Gomes-Pereira, Leonardo, Cunha, Livia Melo Arruda, Gonçalves, Merita Pereira, Vieira, João Victor Soares, Sanches, Mariele Paludetto, Koehler, Natalia, Maluf, Sharbel, Poli, Anicleto, da Silva-Santos, José Eduardo, Assreuy, Jamil, Lemos-Senna, Elenara
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-03-2024
• Subjects: 7-nitroindazole; in vivo toxicity; nanoemulsions; pharmacokinetics; sepsis; 7-nitroindazole; nanoemulsions; pharmacokinetics; sepsis; in vivo toxicity
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2024.106695

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 (NEPEG7NI) and non-pegylated nanoemulsions (NENPEG7NI) 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 Cmax, t1/2, and AUC0-t were significantly increased after administration of the NEPEG7NI, compared to both free 7-NI and NENPEG7NI (p < 0.05). No observable adverse effects were observed after administering the free 7-NI, NEPEG7NI, or NENPEG7NI 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.
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