Discovery permeability screening

Caco-2 monolayer, a model for human intestinal permeability, is commonly used in drug discovery to screen discovery compounds.34,35 The method involves measurement of flux of... 

Use of Caco-2 Cells in Drug Discovery 9.3.1 High-Throughput Permeability Screening... 

The use of in vitro cell culture models for mechanistic studies and as permeability screens for the blood-brain barrier in the pharmaceutical Industry-Background and current status in the drug discovery process. Vascular Pharmacology, 38, 355-364. 

Balimane, P.V., Chong, S., Patel, K., Quan, Y., Timoszyk, J., Han, Y.H., Wang, B., Vig, B. and Faria, T.N. (2007) Peptide transporter substrate identification during permeability screening in drug discovery comparison of transfected MDCK-hPepTl cells to Caco-2 cells. Archives of Pharmacol Research, 30 (4), 507-518. 

Nikolovska-Coleska Z, Xu L, Hu Z, et al. Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. J Med Chem 2004 47 2430-2440. 

From an industrial perspective, quantitative knowledge of the existence of different transporters within the cellular system used in screening procedures is of major importance as it can influence both the predictive value of the permeability coefficients and interpretation of the results. In addition, information on species differences or similarities or discrepancies between cell culture models and animals now provide an important basis for the scaling of data during the early phases of drug discovery for animals or humans [48]. 

There are several approaches to estimating absorption using in vitro methods, notably Caco-2 and MDCK cell-based methods or using methods that assess passive permeability, for example the parallel artificial membrane permeation assay (PAMPA) method. These are reviewed elsewhere in this book. The assays are very useful, and usually have an important role in the screening cascades for drug discovery projects. However, as discussed below, the cell-based assays are not without their drawbacks, and it is often appropriate to use ex vivo and/or in vivo absorption assays. 

Alsenz J, Haenel E (2003) Development of a 7-day, 96-well Caco-2 permeability assay with high-throughput of P-gp screening in drug discovery. Eur J Pharm Biopharm 58 99-105. 

Despite the availability of other cell lines, Caco-2 cells remain the most widely used intestinal cell culture model at present. This model has provided valuable information necessary for lead optimization in the drug discovery process. However, it is important to understand that compounds with high permeability in this model are typically well absorbed, whereas compounds with low solubility and low permeability in this model may not necessarily be poorly absorbed in vivo. Although this type of positive selection limits the usefulness in providing a structure-permeability relationship, the Caco-2 model has the most effect in drug discovery when the screen is implemented early and in conjunction with other types of in vitro and in vivo permeability/absorption screens. 

---