Development of lead drug candidates (having potential pharmacological eff ect) derived from combinatorial synthesis has accelerated the drug discovery process. Th ey have emerged as a quick and easy methods provides data on biological parameters like Potency, Absorption, Distribution, Metabolism, Excretion, Toxicity (ADMET) properties of large number of candidates can be determined simultaneously. However limiting factors for the successful therapeutic application of new drugs is their ability to transport in biological systems namely, over the gastro intestinal tract (GIT), towards the target receptor, or across the blood brain barrier (BBB). Highly standardized in vitro models are therefore required for screening of large number of molecules that gives predictive values for these transport processes. But however, absorption process is influenced by number of factors such as solubility, membrane partitioning, metabolism and transporters. In contrast to less accurate experimentally based in silico predictions of intestinal permeability, done based on their molecular structure, behaviour of molecule with in a biological test system, mechanistic cell lines which gives better data is preferred. Therefore cell lines have evolved as a tool for understanding and evaluating the permeability characteristics of potential lead drug candidates.
PERMEABILITY SCREENING IN DIFFERENT PHASES OF DISCOVERY
Screening of permeability of lead drugs in lead discovery phase (LD) results from High Throughput
Screening (HTS) which provide data and basis for the further modifications of the structure of the molecule in lead optimization phase (LO) which ends with the selection of drug candidate (DC).Hence cell culture models provides a platform for preclinical screening, biopharmaceutical assessments & evaluation of mechanistic purposes.
CELL CULTURES FOR ASSESSMENT OF INTESTINAL PERMEABILITY
Cell culture based models are mainly used for studies of partitioning into membrane, mechanisms of drug absorption and interaction with epithelial proteins (such as transporters and enzymes).These are simple and quick to use, and they reflect different mechanisms involved in absorption process. Paracellular permeability is determined with hydrophobic marker molecules, that do not partition into cell membranes. The functional characteristics of different cell lines currently used in drug discovery are summarized in the table below:
CACO-2 CELL LINE/CELL CULTURE AND TRANSPORT EXPERIMENTS
By virtue of the merits stated in the above CACO-2 screening is most widely used to screen intestinal permeability, to know drug absorption, and to study passive and active diffusion transport of drug molecules