ABSTRACT
The success of a pharmaco-treatment essentially depends on the availability of the drug at the
site of action in the living body. It is mandatory that the intact drug reaches its target site (e.g.,
a specific receptor in the central nervous system) and to an extent that concentrations greater
than the minimal effective concentration (MEC) are provided. If these two prerequisites are
not fulfilled, the therapy fails in vivo, even if the drug has an ideal chemical structure to allow
for optimal interactions with the target structure and pharmacodynamic effects. Some of the
potential reasons for the inability of a drug to reach its site of action are (i) poor aqueous
solubility, (ii) poor permeability across biological barriers, and (iii) rapid clearance out of the
living body. In the first case, the drug remains at the site of administration or-in the case of
oral administration-is not absorbed from the contents of the gastrointestinal tract (GIT). This
is because only dissolved (individualized) drug molecules are able to diffuse and cross the
major natural barriers in a living body (e.g., the GIT mucosa or blood-brain barrier). Poor
permeability through biological barriers can, for example, be caused by a high molecular
weight of the drug (hindering, for instance, diffusional mass transport), poor partitioning into
the barrier (membrane), and/or effective efflux systems (e.g., P-glycoprotein pumps). Rapid
drug inactivation can be due to fast drug metabolism and/or elimination and can also prevent
many drugs from becoming active in vivo, despite of a great therapeutic potential.
Furthermore, in various cases, the undesired side effects of a drug, caused in other parts of the
living body, can be so severe that the administered dose must be limited, eventually to an
extent that does not allow for therapeutic drug concentrations at the site of action. Also in
these cases the therapy fails in vivo, since the drug is distributed throughout the living body,
and not specifically delivered to the target site.
