Receptor-mediated transport of peptide hormones and its importance in the overall hormone disposition in the body.

A remarkable feature of the pharmacokinetics of polypeptide hormones is the contribution of specific binding sites (receptors) to the polypeptide hormone distribution and clearance in the body. The concept of "transport receptor" is now well established, and receptor-mediated endocytosis (RME) is recognized as a general mechanism in the uptake of biologically important peptide hormones. This article focuses on the kinetic analysis of the RME of polypeptides, based mainly upon the observations of the kinetics of epidermal growth factor in the liver. The following points are emphasized: (1) How can we determine the existence and the kinetic constants of polypeptide RME in vivo and in the perfused liver system? A liver perfusion method, the single-pass multiple-indicator dilution technique, has been shown to be suitable for analyzing the dynamics of interaction of peptide hormones with their cell surface receptors. (2) What is the importance of down-regulation of transport receptors to the overall kinetics of polypeptides in vivo? Time profiles of polypeptide plasma concentrations and their surface receptors in the liver after iv administration of epidermal growth factor were simulated with a physiologic pharmacokinetic model that includes kinetic constants representing the interaction of polypeptides and their receptors.