Mass Transport via Cellular Barriers and Endocytosis - Intracellular Delivery: Fundamentals and Applications - page 7

Fig. 1 Schematic illustrating several mechanisms of drug transport across the epithelium
(Reprinted from Gad ( 2008 ). Courtesy of Wiley Publishing Group)
and rapidly distributed to tissues. The kinetics of transport are therefore linear or
first order and the drug absorption can highly depend on the dissolution of the dos-
age form (e.g. tablet, capsule), which can be the rate limiting step (Muranishi 1990 ).
Transport is affected by the physico-chemical characteristics of the drug, such as
lipophilicity, size, and ionization, the latter depending on the pKa of the drug. Since
the molecules have to cross the lipid bilayer, small hydrophobic molecules are
favored. Moreover, uncharged molecules display less repulsion for charged groups
on the membrane surface and are therefore assimilated more easily. Drugs that are
weakly acidic, such as aspirin, are neutral in acidic environments and are therefore
more easily assimilated in the stomach, while weak bases, such as most benzodiaz-
epines, are better absorbed in more alkaline environments such as the duodenum.
However, it is important to emphasize that the main site of absorption in the gastro-
intestinal tract is the small intestine and, in particular, jejunum. Physiologically, this
segment of the gastrointestinal system is designed to absorb the nutrients from
ingested food, while the large intestine's role is to absorb water and ions. The small
intestine is lined with simple columnar epithelium covered with folds, called plicae
circulars. These folds consist of finger-like projections, or villi, characteristic of
epithelial cells, and each cell also has hair-like projections, called microvilli. Each
villus is fed with a network of blood and lymphatic vessels. This very specific
structure has the important function of increasing the surface area available for
absorption of the exogenous substances.
The fundamental equation describing passive drug transport through membranes
is based on Fick's first law, where the constant of proportionality between the drug
flux through a membrane and the gradient of concentration define the effective
permeability coefficient of the drug through the membrane ( P eff ) (Pang 2003 ).