Page - (000298) - in Biomedical Chemistry: Current Trends and Developments

transporters, e.g. P-glycoprotein (PgP), are expressed, which limit the oral absorption of compounds (Fig. 3.3.3) (van de Waterbeemd, 2001). In addition to avoiding the efflux of PgP and metabolism by gut wall enzymes, good permeability is important to maximize the oral absorption of a compound. In general, therapeutic peptides suffer from short half-lives due to rapid degradation by proteolytic enzymes of the GI tract and blood plasma, rapid clearance from the circulation by liver and kidneys, as well as limited permeability across physiological barriers because of their hydrophilic structure (Vlieghe, 2010). Especially CYP3A4 and PgP have been shown to have a significant impact on the bioavailability of peptidic and peptidomimetic drugs (Wacher, 1998). One means of enhancing oral bioavailability is to increase passive diffusion by changing the physiochemical properties (i.e. decreasing the hydrophilicity) of the compound (Wang, 1999). It should be noted that increasing the lipophilicity, in order to improve membrane permeability, can also lead to increased efflux and metabolism. Two other strategies that can be used to improve permeability are reducing hydrogen bonding and decreasing the polarity (Kerns, 2008). Figure 3.3.3: Illustration of the barriers to drug absorption in the GI tract. In the bloodstream, enzymatic hydrolysis by proteolytic enzymes and plasma protein binding (PPB) constitute barriers preventing drugs from penetrating into the tissues. The affinity of a compound to plasma proteins determines the ratio of bound to unbound (“free”) drug in solution, and only the unbound drug can enter the tissues. If a compound has a high binding affinity it can be difficult to achieve concentrations in the tissue sufficient to produce the desired