APPLICATIONS OF THE CACO-2 MODEL IN THE DESIGN AND DEVELOPMENT OF ORALLY-ACTIVE DRUGS - ELUCIDATION OF BIOCHEMICAL AND PHYSICAL BARRIERS POSED BY THE INTESTINAL EPITHELIUM

Oral administration is the most important and preferred route of admin istration for small molecular weight conventional drugs. The overall b ioavailability of an orally administered drug depends on many factors, including the physicochemical properties of the drug as well as the m orphological and biochemical state of the intestinal epithelium. Our u nderstanding of the factors governing oral delivery of drug molecules is far from complete. As a result, the approaches to solve the problem s related to oral drug delivery are often empirical in nature. The mul tifaceted nature of the problems associated with poor oral bioavailabi lity of drug molecules requires a systematic and reductionist approach to understand the underlying factors affecting the bioavailability an d absorption of these molecules. Thus, use of appropriate in vitro mod els is extremely useful in elucidating the role of various physical an d biochemical barriers (such as metabolic enzymes, drug transporters, and the multidrug resistance (MDR) P-glycoprotein) to drug absorption. In this chapter, we have discussed the use of one such in vitro model , i.e. the Caco-2 cells, in elucidating the roles of the physical and biochemical barriers to drug absorption posed by the intestinal epithe lium. By using specific examples, we have illustrated how this improve d understanding about the barriers to drug absorption can be used for the design and development of drug candidates with enhanced oral absor ption.