Drug distribution in the Body I

External Barriers of the Body
Prior to its uptake into the blood (i.e.,
during absorption), a drug has to overcome
barriers that demarcate the body
from its surroundings, i.e., separate the
internal milieu from the external milieu.
These boundaries are formed by
the skin and mucous membranes.
When absorption takes place in the
gut (enteral absorption), the intestinal
epithelium is the barrier. This singlelayered
epithelium is made up of enterocytes
and mucus-producing goblet
cells. On their luminal side, these cells
are joined together by zonulae occludentes
(indicated by black dots in the inset,
bottom left). A zonula occludens or
tight junction is a region in which the
phospholipid membranes of two cells
establish close contact and become
joined via integral membrane proteins
(semicircular inset, left center). The region
of fusion surrounds each cell like a
ring, so that neighboring cells are welded
together in a continuous belt. In this
manner, an unbroken phospholipid
layer is formed (yellow area in the schematic
drawing, bottom left) and acts as
a continuous barrier between the two
spaces separated by the cell layer – in
the case of the gut, the intestinal lumen
(dark blue) and the interstitial space
(light blue). The efficiency with which
such a barrier restricts exchange of substances
can be increased by arranging
these occluding junctions in multiple
arrays, as for instance in the endothelium
of cerebral blood vessels. The connecting
proteins (connexins) furthermore
serve to restrict mixing of other
functional membrane proteins (ion
pumps, ion channels) that occupy specific
areas of the cell membrane.
This phospholipid bilayer represents
the intestinal mucosa-blood barrier
that a drug must cross during its enteral
absorption. Eligible drugs are those
whose physicochemical properties allow
permeation through the lipophilic
membrane interior (yellow) or that are
subject to a special carrier transport
mechanism. Absorption of such drugs
proceeds rapidly, because the absorbing
surface is greatly enlarged due to the
formation of the epithelial brush border
(submicroscopic foldings of the plasmalemma).
The absorbability of a drug is
characterized by the absorption quotient,
that is, the amount absorbed divided
by the amount in the gut available
for absorption.
In the respiratory tract, cilia-bearing
epithelial cells are also joined on the
luminal side by zonulae occludentes, so
that the bronchial space and the interstitium
are separated by a continuous
phospholipid barrier.
With sublingual or buccal application,
a drug encounters the non-keratinized,
multilayered squamous epithelium
of the oral mucosa. Here, the cells
establish punctate contacts with each
other in the form of desmosomes (not
shown); however, these do not seal the
intercellular clefts. Instead, the cells
have the property of sequestering phospholipid-
containing membrane fragments
that assemble into layers within
the extracellular space (semicircular inset,
center right). In this manner, a continuous
phospholipid barrier arises also
inside squamous epithelia, although at
an extracellular location, unlike that of
intestinal epithelia. A similar barrier
principle operates in the multilayered
keratinized squamous epithelium of the
outer skin. The presence of a continuous
phospholipid layer means that
squamous epithelia will permit passage
of lipophilic drugs only, i.e., agents capable
of diffusing through phospholipid
membranes, with the epithelial thickness
determining the extent and speed
of absorption. In addition, cutaneous absorption
is impeded by the keratin
layer, the stratum corneum, which is
very unevenly developed in various areas
of the skin.