ABSTRACT
The oral route of administration is preferred for many classes of drugs; ease and patient compliance are the main reasons. Making reliable estimates of oral bioavailability in humans for the selection of the best developmental candidates are a considerable challenge to the pharmaceutical industry. In recent years, several promising in vitro models became available for the study of the absorption potential of new compounds (1). Systemic bioavailability is influenced by a variety of factors (Table 1), with poor solubility, poor permeation, intestinal and liver metabolism, and P-glycoprotein (P-gp)-mediated efflux being among the most common detrimental influences on drug absorption. In this chapter we focus attention on the physicochemical properties of a drug and their influence on the overall bioavailability (2). These properties can have a particularly important effect on the absorption process (Fig. 1). The main uptake mechanism through mucosal membranes is by passive diffusion, using the transcellular pathway (A 1). However, several alternative processes (A0, A2-A6), all of which may affect the final fraction absorbed, need to be considered. These processes may not be independent, and they partly take place in parallel. Often the relative weights (ao-a6) of the contributions of each of these potential processes is unknown. Membrane diffusion by the trans-and paracellular pathway is a physicochemical process; therefore, physicochemical properties are believed to have an important influence on these membrane transport
processes. Molecular properties (i.e., structural features and physicochemical properties) can be assessed by experimental and computational approaches. As will be demonstrated in this chapter, by combining these two, reliable estimates of intestinal permeability can be made. However, besides using computation and physicochemical methods, additional in vitro and in vivo studies should be performed to make confident estimates of absorption behavior in humans.
