Pharmacokinetic Aspects of Peptide Delivery and Targeting: Importance of Receptor-Mediated Endocytosis

Abstract

A remarkable feature of the disposition of polypeptide hormones is the contribution of specific binding sites (receptors) on the cell-surface to their clearance in the body. Receptor-mediated endocytosis (RME) is now well recognized as a polypeptide clearance system. In addition, drug targeting utilizing RME is expected to have promise as a drug delivery system (DDS) to carry some drug specifically into the target cell expressing receptors on its plasma membrane. Therefore, it is important to analyze the RME process kinetically, both to clarify the pharmacokinetics of polypeptide itself and to estimate the efficiency of drug targeting via polypeptide receptors. We have been studying the hepatic handling of epidermal growth factor (EGF) and hepatocyte growth factor (HGF) using perfused rat liver, isolated rat hepatocytes, and primary cultured rat hepatocytes. Kinetic analysis of hepatic clearance of EGF enabled us to determine the kinetic parameters for the construction of a kinetic model for RME. Based on such a kinetic model, we can discuss the contribution of each process in RME on the efficiency of drug targeting into the cell. Not only RME, but also a non-specific uptake mechanism was found to contribute to hepatic HGF disposition. This finding was important piece of information in developing a DDS for HGF, aimed at decreasing such non-specific uptake, with the result of prolonged plasma residence time.