External Barriers of the Body

Prior to its uptake into the blood (i.e.,during absorption), a drug has to over-come barriers that demarcate the bodyfrom its surroundings, i.e., separate theinternal milieu from the external mi-lieu. These boundaries are formed bythe skin and mucous membranes.When absorption takes place in thegut (enteral absorption), the intestinalepithelium is the barrier. This single-layered epithelium is made up of ente-rocytes and mucus-producing gobletcells. On their luminal side, these cellsare joined together by zonulae occlu-dentes (indicated by black dots in the in-set, bottom left).


A zonula occludens ortight junction is a region in which thephospholipid membranes of two cellsestablish close contact and becomejoined via integral membrane proteins(semicircular inset, left center). The re-gion of fusion surrounds each cell like aring, so that neighboring cells are weld-ed together in a continuous belt. In thismanner, an unbroken phospholipidlayer is formed (yellow area in the sche-matic drawing, bottom left) and acts asa continuous barrier between the twospaces separated by the cell layer – inthe case of the gut, the intestinal lumen(dark blue) and the interstitial space(light blue).

The efficiency with whichsuch a barrier restricts exchange of sub-stances can be increased by arrangingthese occluding junctions in multiplearrays, as for instance in the endotheli-um of cerebral blood vessels. The con-necting proteins (connexins) further-more serve to restrict mixing of otherfunctional membrane proteins (ionpumps, ion channels) that occupy spe-cific areas of the cell membrane.This phospholipid bilayer repre-sents the intestinal mucosa-blood bar-rier that a drug must cross during its en-teral absorption. Eligible drugs are thosewhose physicochemical properties al-low permeation through the lipophilicmembrane interior (yellow) or that aresubject to a special carrier transportmechanism.

Absorption of such drugs proceeds rapidly, because the absorbingsurface is greatly enlarged due to theformation of the epithelial brush border(submicroscopic foldings of the plasma-lemma). The absorbability of a drug ischaracterized by the absorption quo-tient, that is, the amount absorbed di-vided by the amount in the gut availablefor absorption.In the respiratory tract, cilia-bear-ing epithelial cells are also joined on theluminal side by zonulae occludentes, sothat the bronchial space and the inter-stitium are separated by a continuousphospholipid barrier.With sublingual or buccal applica-tion, a drug encounters the non-kerati-nized, multilayered squamous epitheli-um of the oral mucosa.

Here, the cellsestablish punctate contacts with eachother in the form of desmosomes (notshown); however, these do not seal theintercellular clefts. Instead, the cellshave the property of sequestering phos-pholipid-containing membrane frag-ments that assemble into layers withinthe extracellular space (semicircular in-set, center right). In this manner, a con-tinuous phospholipid barrier arises alsoinside squamous epithelia, although atan extracellular location, unlike that ofintestinal epithelia. A similar barrierprinciple operates in the multilayeredkeratinized squamous epithelium of theouter skin. The presence of a continu-ous phospholipid layer means thatsquamous epithelia will permit passageof lipophilic drugs only, i.e., agents ca-pable of diffusing through phospholipidmembranes, with the epithelial thick-ness determining the extent and speedof absorption. In addition, cutaneous ab-sorption is impeded by the keratinlayer, the stratum corneum, which isvery unevenly developed in various are-as of the skin.