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While the intestinal epithelium provides a protective barrier to the entry of intestinal pathogens, it also regulates and restricts the absorption of orally administered drugs and macromolecules. The ability to dose therapeutics orally confers a number of advantages when compared to alternative routes, such as parenteral administration. These advantages include easier administration and the avoidance of pain and discomfort associated with injectable formulations (which typically leads to increased patient compliance), prevention of possible infections due to reuse of needles, as well as less complicated and less expensive development strategies for pharmaceutical companies due to the lack of necessary sterile formulations.

For a hydrophilic drug or macromolecule that is not recognized by a carrier, oral absorption is poor because the drug cannot partition into the hydrophobic membrane and traverse the epithelial barrier via the transcellular pathway, and transport via the paracellular pathway is severely restricted by the very low surface area available for transport, as well as

the presence of tight junctions (Figure 1.1, page 4)). For example, the broad spectrum antibiotic cefoxitin and the antiviral zanamivir, both hydrophilic drug molecules, have oral bioavailabilities less than 5%, precluding their use in conventional oral formulations and limiting their clinical utility. Strategies to develop oral formulations for hydrophilic drug candidates typically include chemical modifications that provide increased lipophilicity to promote increased transcellular permeation, or that provide increased affinity for transporters to promote carrier mediated absorption (i.e. prodrugs). Unfortunately, structural changes often lead to reduced potency towards the intended pharmacological target, necessitating complete release of the prodrug moiety from the parent drug, and complicating drug design and the drug development process. Furthermore, this strategy is not typically useful for macromolecules such as insulin, heparin, or salmon calcitonin, as their polar surface area is simply too large to mask with a small chemical modification. An alternative approach to improve the oral absorption of hydrophilic drugs is to transiently alter the physical barrier imposed by the intestine, through controlled and reversible opening of tight junctions. This approach has a distinct advantage over the development of prodrugs, as it would be universally applicable to all hydrophilic drugs and macromolecules; however, it has generally been met with significant resistance in the pharmaceutical industry. A major concern stems from the fact that many intestinal pathological disorders are characterized by leaky epithelia, including inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis339, as

well as intestinal cancers340; therefore, there is a general fear that tight junction modulation is

an approach to increase paracellular permeability that may lead to pathological outcomes, and therefore, should not be considered as a pharmacological approach. This fear is partly substantiated by the fact that a number of bacterial enterotoxins have considerable effects on

tight junction function. For example, clostridium perfringens enterotoxin (CPE)341 and zonula

occludens toxin (ZOT)342 cause food poisoning and diarrhea in humans, effects thought to be

mediated by their specific modulation of tight junctions343, 344. Interestingly however, specific

amino acid sequences of these two toxins have been shown to be responsible for the observed effects on tight junction function (i.e. c-CPE and ΔG respectively), and when administered as small peptides, lack the observed toxicity associated with each enterotoxin, suggesting that tight junctions can be modulated without significant adverse events. Currently, these two peptides represent the most promising PPEs identified to date345, 346. A second major concern

regarding the use of PPEs in humans stems from a general lack of understanding about how mature epithelial tight junctions are formed and regulated; however, in recent years, significant advancement in our understanding of how the tight junction is organized and regulated physiologically have made this approach to increasing oral absorption an achievable reality, and have begun to ameliorate these safety concerns.

Unfortunately, there has not yet been a safe and effective PPE approved for clinical use in humans in the United States. Many of the known PPEs have been found to lack selectivity, i.e. there is little separation between their potency as permeability enhancers and their potency to cause local intestinal toxicity, suggesting that their enhancement effect may be the result of erosion of the intestinal epithelium. The PPEs with these characteristics are typically amphiphilic, and their physicochemical properties suggest a propensity to accumulate in cell membranes, a characteristic that likely contributes to the lack of separation between efficacy and toxicity (Liu et al., 1999). Bile acids347_{, fatty acids}298_{, acylcarnitines}348_,

alkylphosphocholines334, and glyceride analogs349 all fall into this category of PPEs. Most of

a strategy of rationale drug design, likely due to a lack of validated targets known to regulate tight junction function. Recent advances surrounding the biochemistry and physiology of junctional complexes have led to renewed interest in these complex subcellular structures, and continued research in this area should soon provide a number of pharmacological targets to realize the potential for transient and reversible opening of intestinal tight junctions to allow increased absorption of orally administered therapeutics.