The Paracellular Absorption Route

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INTESTINAL ABSORPTION ENHANCEMENT VIA THE
PARACELLULAR ROUTE: A TARGET FOR DRUG DELIVERY

Abstract
Peroral delivery of hydrophilic drugs is one of the greatest challenges in biopharmaceutical research.
Hydrophilic drugs usually present low bioavailability after oral administration. One of the causes of
this low bioavailability is their poor intestinal permeation through the paracellularpathway. In fact,
this pathway is actually restricted by the presence of tight junctions at the apical side of the
enterocytes. In the last few years, great interest has focused on the structure and cellular regulation of
tight junctions, materializing in more in-depth knowledge of this intestinal barrier. Simultaneously,
and on the basis of this understanding, continuous efforts are beingmade to develop agents that can
modulate tight junctions and magnify the paracellular permeability of hydrophilic compounds without
causing significant intestinal damage. This review focuses on the strategies to improve paracellular
permeation of poorly absorbed drugs as a way to enhance their bioavailability after oral
administration. Most of the research on this subject has been carried outusing in vitro models (mainly
Caco-2 cell monolayers), which yield useful information on the potential effects and mechanisms of
action of absorption-enhancing compounds. However, in vivo studies, which are much more scarce,
are needed to confirm the effects of potential enhancers and to evaluate the suitability of including
these compounds as excipients in drug formulation. In this sense, wereview the in vitro and in situ
studies involving the most promising paracellular permeation enhancers (e.g., medium chain fatty
acids and chitosan and its derivatives), analyzing the degree of drug absorption enhancement achieved,
as well as the potential associated toxicity. The results obtained using these methodologies are in turn
compared with those reported in vivo. In addition, thefindings of recent absorption enhancers, such as
zonula occludens toxin or thiolated polymers, are reviewed.
Keywords: paracellular permeation enhancement, tight junctions, sodium caprate, chitosan, oral
bioavailability, drug delivery.
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INTRODUCTION
The pharmaceutical industry invests great sums of money in the development of drugs that
can be effective in application to pathologies that affectmajor population groups or in treating
new diseases. In this challenging task, and apart from the pharmacological effects which
represent the first development step, it is of great relevance to consider the biopharmaceutical
and pharmacokinetics properties of the drug - particularly those concerning intestinal
absorption and bioavailability (BA) after oral administration. Obviously, the oralroute is the
preferred administration route, and it must be taken into account that some of the newer
promising drugs cannot be developed as oral products because of their null or scarce
bioavailability. In general, these are hydrophilic compounds, of medium to high-molecular
weight, and sometimes containing strongly charged functional groups - implying that
transport across the intestinalbarrier occurs essentially via the paracellular pathway [1]. The
contribution of the latter to intestinal absorption is considered to be small, however, since this
pathway occupies less than 0.1% of the total surface area of the intestinal epithelium [2], and
the presence of tight junctions (TJ) between the epithelial cells limits drug absorption.
Therefore, for the above mentioned drugs the maincause of low bioavailability is their poor
intestinal permeability.
In the last decade many efforts have been made to increase the paracellular transport of less
absorbable drugs - the use of enhancers being the most promising and studied strategy [3,4].
Our understanding of tight junction physiology and regulation has increased in recent years
[5], thus facilitating the search for...