As with any drug class, the medicinal chemist and pharmacist must be concerned with the absorption, distribution, metabolism, and excretion (ADME) parameters of protein drugs. Biotechnology-produced drugs add complexities that are not encountered with "traditional" low-molecular-weight drug molecules. ADME parameters are necessary to compute pharmacokinetic and pharmacodynamic parameters for a given protein. As for any drug, these parameters are essential in calculating the optimum dose for a given response, determining how often to administer the drug to obtain a steady state, and adjusting the dose to obtain the best possible residence time at the receptor (pharmacodynamic parameters).
Delivery of drugs with the molecular weights and properties of proteins into the human body is a complex task. The oral route cannot be used with a protein because the acidity of the stomach will catalyze its hydrolysis unless the drug is enteric coated. Peptide bonds are chemically labile, and proteolytic enzymes that are present throughout the body can attack and destroy protein drugs. Hydrolysis and peptidase decomposition also occur during membrane transport through the vascular endothelium, at the site of administration, and at sites of reaction in the liver, blood, kidneys, and most tissues and fluids of the body. It is possible to circumvent these enzymes by saturating them with high concentrations of drug or by coadministering peptidase inhibitors. Oxidative metabolism of aromatic rings and sulfur oxidation can also occur. Proteins typically decompose into small fragments that are readily hydrolyzed, and the individual amino acids are assimilated into new peptides. A potentially serious hindrance to a pharmacokinetic profile is the tendency of proteins administered as drugs to bind to plasma proteins, such as serum albumin. If this happens, they enter a new biodistribution compartment from which they may slowly exit. Presently, the routes of administration that are available for protein drugs are largely subcutaneous (SC) and intramuscular (IM). Much ongoing research is targeted at making peptide drugs more bioavailable. An example of this is conjugation of interleukin-2 (IL-2) with PEG. These so-called pegylated proteins tend to have a slower elimination clearance and a longer i1/2 than IL-2 alone. Another strategy being used is the installation of a prosthetic sugar moiety onto the peptide. The sugar moiety will adjust the partition coefficient of the drug, probably making it more water soluble.
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