Evaluation of the Pharmacokinetics of the Pancreastatin Inhibitor PSTi8 Peptide in Rats: Integration of In Vitro and In Vivo Findings.

Guru R Valicherla,Roshan A Katekar,Sandeep K Singh,Muhammad Wahajuddin,Anees A Syed,Shailesh Dadge,Athar Husain,Mohammed Riyazuddin,Jiaur R Gayen

doi:10.3390/molecules27020339

Abstract

PSTi8 is a pancreastatin inhibitory peptide that is effective in the treatment of diabetic models. This study investigates the pharmacokinetic (PK) properties of PSTi8 in Sprague Dawley rats, for the first time. In vitro and in vivo PK studies were performed to evaluate the solubility, stability in plasma and liver microsomes, plasma protein binding, blood–plasma partitioning, bioavailability, dose proportionality, and gender difference in PK. Samples were analyzed using the validated LC-MS/MS method. The solubility of PSTi8 was found to be 9.30 and 25.75 mg/mL in simulated gastric and intestinal fluids, respectively. The protein binding of PSTi8 was estimated as >69% in rat plasma. PSTi8 showed high stability in rat plasma and liver microsomes and the blood–plasma partitioning was >2. The bioavailability of PSTi8 after intraperitoneal and subcutaneous administration was found to be 95.00 ± 12.15 and 78.47 ± 17.72%, respectively, in rats. PSTi8 showed non-linear PK in dose proportionality studies, and has no gender difference in the PK behavior in rats. The high bioavailability of PSTi8 can be due to high water solubility and plasma protein binding, low clearance and volume of distribution. Our in vitro and in vivo findings support the development of PSTi8 as an antidiabetic agent.

Highlights

In the 21st century, diabetes is one of the rapidly growing health challenges in the world
The intra- and inter-day precision of PSTi8 were found between 2.29–3.64% and 5.73–8.43%, respectively
The PSTi8 peptide was found to be stable in rat plasma and liver microsomes

Summary

Introduction

In the 21st century, diabetes is one of the rapidly growing health challenges in the world. To date, existing drugs cannot completely cure type 2 diabetes, but they can manage glucose levels and prevent complications associated with the different organs [3,4]. There is a strong interest in the discovery and development of more effective drugs for the treatment of type 2 diabetes. The PSTi8 peptide showed potent antidiabetic activity in several preclinical diabetes and insulin resistance (IR) models, such as diet-induced diabetes and IR mice, db/db mice, diet-induced IR postmenopausal rats, dexamethasone induced type 2 diabetes mice and chronic hyperinsulinemia mice [5,7,8,9,10]. PSTi8 is a highly potent antidiabetic peptide and the chronic dose used for antidiabetic activity in mice and rat models was 2 and 1 mg/Kg, respectively [5,7]

Methods

Results

Conclusion