Drug dosing most often involves the oral route of administration. The vast majority of drug dosage forms are designed for oral ingestion, primarily for ease of administration. It should be recognized, however, that this route may result in inefficient and erratic drug therapy. Whenever a drug is ingested orally (or by any nonvascular route), one would like it to have rapid and complete absorption into the bloodstream for the following reasons:

1. Assuming that there is some relationship between drug concentration in the body and the magnitude of the therapeutic response (which is often the case), the greater the concentration achieved, the larger the magnitude of response.

2. In addition to desiring therapeutic concentrations, one would like to obtain these concentrations rapidly. The more rapidly the drug is absorbed, in general, the sooner the pharmacological response is achieved.

3. In general, one finds that the more rapid and complete the absorption, the more uniform and reproducible the pharmacological response becomes.

4. The more rapidly the drug is absorbed, the less chance there is of drug degradation or interactions with other materials present in the gastrointestinal tract (GIT).

In a broad sense, one can divide the primary factors that influence oral drug absorption and thus govern the efficacy of drug therapy into the following variables: physicochem-ical, physiological, and dosage form. For the most part, these variables will determine the clinical response to any drug administered by an extravascular route. Although often the total response to a drug given orally is a complex function of the aforementioned variables interacting together, the present discussion is limited primarily to the first two categories involving physicochemical and physiological factors. Dosage form variables influencing the response to a drug and the effect of route of administration are discussed in chapters 4, 5 and 6.

The vast majority of drugs in current use and those under development are relatively simple organic molecules obtained from either natural sources or by synthetic methods. It is important to note, however, the virtual revolution in development of new therapeutic entities; those based upon the incredible advances being made in the application of molecular biology and biotechnology. These new drugs, especially peptides, proteins, and monoclonal antibodies are not the traditional small organic molecules stressed in this chapter. Indeed, those compounds have unique physicochemical properties, which are quite different from those of small organic molecules, and they offer remarkable challenges for drug delivery. As a result, new and more complex physical delivery systems are being designed in conjunction with an examination of other, less traditional routes of administration (e.g., nasal, pulmonary, transdermal). Because of issues of instability in the GIT and poor intrinsic membrane permeability, it appears unlikely that these new biologically-based drugs will employ the oral route for administration. Numerous strategies are being explored, but to date relatively little success has been achieved (1). One approach that shows promise involves conjugating a poorly absorbed compound to a so-called molecular transporter. The latter are oligomers of arginine that undergo active cellular uptake (2,3).

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