Absorption and Bioavailability

Because most proteins are susceptible to protease degradation and denaturation in biologic fluids, most biopharmaceuticals must be administered by intravenous, intramuscular, or subcutaneous injection (see Table 5.5). High concentrations of proteases are found in the gastrointestinal tract, nasal mucosa, bronchioles, and alveoli, which severely limit the bio-availability of protein pharmaceuticals after oral, intranasal, and inhalation administration. Diffusional barriers to the passage of relatively large macromolecules preclude transdermal and mucosal administration of protein pharmaceuticals. Research is under way to develop methods that will protect protein drugs from proteolysis and improve transmembrane diffusion.

Tissue Distribution of Biopharmaceuticals. By design, monoclonal antibodies exhibit high-affinity binding to specific antigenic epitopes. These epitopes are present somewhere in the body; perhaps on cell surfaces in healthy or cancerous tissue. In an ideal situation, a monoclonal antibody would distribute only to the high-affinity binding sites in target tissues. Invariably, however, any protein molecule, even a monoclonal antibody, distributes into nontarget tissue sites, which can account for a major fraction of the dose. Nonspecific distribution could give rise to toxicity and loss of potency.

Distribution of proteins to tissues is controlled by the permeability (porosity) of the vasculatures and thereby influenced by the molecular size of the protein. A protein of greater than 150 kDa (~50nm) in size will have limited distribution and may be restricted to blood volume. Infrequently a large protein has amino acid recognition sequences that allow passage across epithelial cells lining the vasculatures by transcy-tosis, a process that allows directional transport of protein into and out of a cell.

Another factor influencing nonspecific tissue distribution is the carbohydrate portion of the IgG molecule, which is attached to the therapeutic protein via an N-linked glycan in the constant domain (Fc). Loss of terminal sialylated residues on the carbohydrate of IgG exposes galactose and promotes receptor-mediated binding of IgG to hepatocytes. Consequently this results in an increase in nonspecific distribution to the liver. Details of desialyation of IgG and its consequences are discussed in Chapter 10. Other glycoproteins may exert similar mechanisms of nonspecific distribution.

Loss of sialylated residues may also expose terminal mannose residues, which are attractive targets for phagocytic cells. Phagocytic cells with mannose receptors are highly effective in further clearing the partially degraded IgG. While exposure of mannose residues may reduce the therapeutic effect of a monoclonal antibody by accelerating phagocytic elimination processes, phagocytosis may provide a controlled duration of action and thereby minimize toxicity. For example, thrombolytic agents designed to act at the site of a thrombus may cause bleeding if extensive nonspecific distribution occurs. Phagocytic cells in blood and liver, such as macrophages and Kupfer cells, limit nonspecific distribution of these agents.

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