In vitro models for selection of development candidates. Permeability studies to define mechanisms of absorption enhancement

Considerable attention has been given to alternative strategies for improving the absorption of peptides and hydrophilic drugs across the intestinal epithelium. One approach to overcoming this restriction is to co-administer drugs with absorption enhancers. Although in many cases, improvements in drug absorption by enhancers have been ascribed to mucosal damage, it now appears that enhancement can be separated from damage by manipulating the concentration and exposure of the epithelium to these agents. There are a number of agents that increase mucosal permeability in a reversible manner and without overt alterations to the intestinal mucosa. Increasing evidence suggests the most promising enhancers alter paracellular rather than transcellular permeability of the mucosal epithelium. Several classes of agents that have been tested as absorption promoters are discussed, including experimental evidence as to their mechanism of action and toxicity. The structural and functional features of cell tight junctions are also addressed, particularly, as they are involved in the regulation of paracellular permeability. In addition, results from studies performed using a variety of in vitro model systems are presented that have helped elucidate the specific cellular mechanisms of absorption enhancement. The future prospects of absorption enhancers is promising. However, a number of safety concerns and formulation design issues must be considered before the application of absorption enhancers to routine oral drug delivery in humans can be realized.