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 im proving the absorption of peptides and hydrophilic drugs across the in testinal 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 m ucosal damage, it now appears that enhancement can be separated from d amage by manipulating the concentration and exposure of the epithelium to these agents. There are a number of agents that increase mucosal p ermeability in a reversible manner and without overt alterations to th e intestinal mucosa. Increasing evidence suggests the most promising e nhancers alter paracellular rather than transcellular permeability of the mucosal epithelium. Several classes of agents that have been teste d as absorption promoters are discussed, including experimental eviden ce as to their mechanism of action and toxicity. The structural and fu nctional features of cell tight junctions are also addressed, particul arly, as they are involved in the regulation of paracellular permeabil ity. In addition, results from studies performed using a variety of in vitro model systems are presented that have helped elucidate the spec ific cellular mechanisms of absorption enhancement. The future prospec ts of absorption enhancers is promising. However, a number of safety c oncerns and formulation design issues must be considered before the ap plication of absorption enhancers to routine oral drug delivery in hum ans can be realized.