In vitro permeability of peptidomimetic drugs: The role of polarized efflux pathways as additional barriers to absorption

Abstract Cellular efflux pathways function to remove both endogenous and exogenous substances from the cell. In the case of a polarized cellular barrier, such as the epithelium, these pathways serve an excretory or secretory role in transporting solutes out of tissue. Although well recognized in organs typically associated with drug excretion such as liver and kidney, similar transport pathways have been found in other tissues including the intestinal mucosa and the endothelial cells comprising the blood-brain barrier. Current evidence suggests that these systems may act as barriers to drug absorption into the tissues in which they are found. More recent studies have shown that hydrophobic peptides such as cyclosporin A are substrates for polarized efflux. In this review we examine the evidence for these mechanisms as absorption barriers and the use of in vitro transport models for characterizing this phenomenon. The presence of such pathways may help explain the poor membrane permeability of peptides which, along with metabolism, contributes to their poor in vivo performance.