ITABLE 51 Types of glycosylationN or Olinkage on some protein pharmaceuticals produced in mammalian cells

Protein Pharmaceuticals

Glycosylation Linkage to Peptide Back bone"

Erythropoietin (EPO)

Factors VII, VIII, IX, and X

Granulocyte colony-stimulating factor (G-CSF)

Granulocyte-macrophage colony-stimulating factor (GM-CSF)

Interleukin-2 (IL-2)

Interferon-alfa (IFN-a)

Interferon-beta (IFN-b)

Interferon-gamma (IFN-g)

IgG, including monoclonal antibodies

Tissue plasminogen activator (tPA)

N- and O-linked

N- and O-linked

O-linked

N-linked

O-linked

N- and O-linked

N-linked

N-linked

N-linked

N-linked

"N-linked;addition of glycosyl group through amino linkage of sugar residues attached to asparagine amino-acid residue on protein. O-linked;addition of glycosyl group through threonine or serine amino-acid residue on protein.

percentage of the dose reaching the circulation is the bioavailability of a drug for a specified route of administration. Low bioavailability of a drug after oral administration could be the result of poor lipid solubility, poor dissolution in the gastrointestinal tract, or extensive metabolism in the gut and liver. Low bioavailablity after subcutaneous or intramuscular administration may be the result of precipitation or degradation of the product at the injection site.

When a drug reaches the circulation, it quickly distributes outside the capillary beds into well-perfused tissues but may distribute slowly or not at all to less-accessible tissues protected by barriers, such as the brain. The volume of distribution is the ratio of the amount of drug in the body divided by the drug concentration in plasma once a pseudo-equilibrium is established between blood and tissues. For small molecules, a low volume of distribution generally signifies extensive plasma protein binding that restricts distribution outside the capillary bed, while a large volume of distribu tion, often exceeding the total volume of body water, usually means extensive tissue binding. For large molecules such as proteins and peptides greater than 1.5 kDa, distribution is restricted to blood volume (about 5 liters). Smaller biopharmaceuticals may diffuse into extravascular fluid and reach a volume of distribution of about 20 to 30 liters. The volume of distribution of several proteins of therapeutic interest is listed in Table 5.2.

Because plasma protein and tissue binding influences the amount of drug in each body compartment, the volume of distribution of a drug may be dose dependent (nonlinear). A limited number of binding sites may result in capacity-limited binding in plasma or tissues. Transport from the blood may also be capacity limited. Examples of dose-dependent volume changes show that the volume of distribution of recombinant human tumor necrosis factor (TNF) alpha decreases sharply with a fourfold increase in dose and that the volume of distribution of recombinant human DNase,

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