Hepatic Elimination

The liver plays an important role in the removal of proteins from the systemic circulation. Uptake of peptides and proteins from the blood into hepatocytes occurs by two mechanisms (9): receptor-mediated endocytosis (RME) and non-selective pinocytosis

RME can lead to saturable clearance or nonlinear pharmacokinetics for peptide and protein drugs (3). In RME, circulating proteins are taken up by specific hepatic receptors (9). Insulin and epidermal growth factor are examples of RME. Receptor-mediated uptake for some proteins is so extensive that the clearance of such macromolecules can equal the liver blood flow (4).

Pinocytosis, on the other hand, is a nonspecific, nonsaturable, noncarrier-mediated form of membrane transport; this type of transport mechanism involves vesicular uptake of bulk fluid into cells from the surrounding medium (13). Proteins taken up by this mechanism are internalized according to their concentration within plasma (9). Polymer conjugates, some antigen-antibody complexes, some glycoproteins, and pancreatic proteins are examples of proteins cleared from plasma by pinocytosis (9).

Some proteins can also be cleared from the systemic circulation by biliary excretion. Insulin and epidermal growth factor are examples of therapeutic proteins, which are excreted in the bile (14). These proteins may undergo partial proteolysis prior to biliary excretion (14).

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