Pharmacokinetic and safety profile of PT109B, a novel multi-targeted compound against Alzheimer's disease

• Published in: European journal of pharmaceutical sciences Vol. 188; p. 106532
• Main Authors: Wu, Yufeng, Yang, Yang, Liu, Jingyu, Li, Yagang, Pi, Rongbiao, Ren, Yu, Jiang, Tianyang, Wang, Yuran, Zhong, Guoping
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2023
• Subjects: Acute toxicity; Pharmacokinetic; PT109B; Tissue distribution; UPLC-MS/MS; UPLC-MS/MS; Tissue distribution; PT109B; Pharmacokinetic; Acute toxicity
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2023.106532

PT109B, 5-(1,2-dithiolan-3-yl)-N-((1r,4r)-4-(isoquinolin-5-ylamino) cyclohexyl) pentanamide, a novel compound structurally related to Fasudil, has been reported as a promising candidate for treating Alzheimer's disease. To investigate the pharmacokinetics and acute toxicity of PT109B in rodents, we first developed and validated a UPLC-MS/MS analytical method to detect PT109B concentration in the biological matrix. The proposed method could separate and quantify the PT109B with good precision and accuracy. The pharmacokinetic results showed that the concentrations of PT109B in rat plasma increased with the dose, but not proportionally. Meanwhile, the double-peak phenomenon disappeared when decreasing the oral administration dosage. In addition, we found that PT109B could be detected in the central nervous system, and highly distributed in the liver and kidney. At the same time, the gender difference of PT109B in rats was observed, and the exposure of PT109B in female rats was significantly higher than that in male rats after oral administration. Finally, we found that oral administration of 750 mg/kg PT109B to C57 BL/6 mice caused significant liver injury in females, which was specifically manifested as hepatomegaly, increased liver coefficient, and hepatocyte ballooning. However, no significant damage was observed in other organs, which may be related to the distribution of PT109B in the liver. In summary, we first established a UPLC-MS/MS method for the analysis of PT109B in a biological matrix and described the characteristics of pharmacokinetics, and acute toxicity of PT109B in rodents, providing a sufficient pharmacokinetic basis for further study of PT109B. [Display omitted]