Caco-2 cell permeability

Fujikawa M, Ano R, Nakao K, Shimizu R and Akamatsu M. Relationships between structure and high-throughput screening permeability of diverse drugs with artificial membranes application to prediction of Caco-2 cell permeability. Bioorg Med Chem 2005 13 4721-32. 

Van de Waterbeemd, H., Camenisch, G., Folkers, G., Raevsky, O. A. Estimation of Caco-2 cell permeability using calculated molecular descriptors. Quant. Struct.-Act. Relat. 1996, 15, 480-490. 

Calculated molecular descriptors including H-bond parameters were used for QSAR studies on different types of permeabiUty. For example, the new H-bond descriptor characterizing the total H-bond ability of a compound, was successfully appUed to model Caco-2 cell permeability of 17 drugs [30]. A similar study on human jejunal in vivo permeabiUty of 22 structurally diverse compounds is described in Ref. [62]. An exceUent one-parameter correlation of human red ceU basal permeabiUty (BP) was obtained using the H-bond donor strength [63] ... 

Yazdanian, M. Glynn, S. L. Wright, J. L. Hawi, A., Correlating partitioning and Caco-2 cell permeability of stucturally diverse small molecular weight compounds, Pharm. Res. 15, 1490-1494 (1998). 

Figure 6 Correlation of the fraction of dose absorbed with Caco-2 cell permeability obtained in four different laboratories ( , , A, and A). Qualitatively similar correlations were established in all four laboratories, but the data are not directly comparable due to quantitative differences in the permeability of the Caco-2 monolayers. (From Ref. 38 with kind permission from Elsevier Science-NL, Amsterdam.)...

Liang, E., K. Chessic, and M. Yazdanian. Evaluation of an accelerated Caco-2 cell permeability model, J. Pharm. Sci. 2000, 89, 336-345... 

M., Evaluation of an accelerated Caco-2 cell permeability model,... 

Norinder, U., Osterberg, T., Arturs-son, P., Theoretical calculation and prediction of Caco-2 cell permeability using MolSurf parametrization and PLS statistics, Pharm. Res. 1997, 24, 1786-1791. 

Fujiwara, S., Yamashita, F., and Hashida, M., Prediction of Caco-2 cell permeability using a combination of MO-calculation and neural network, bit. J. Pharm., 2002, 237, 95— 105. 

Ren, S. and Lien, E. J., Caco-2 cell permeability vs human gastrointestinal absorption QSPR analysis,... 

In the following section, the calculation of the VolSurf parameters from GRID interaction energies will be explained and the physico-chemical relevance of these novel descriptors demonstrated by correlation with measured absorption/ distribution/metabolism/elimination (ADME) properties. The applications will be shown by correlating 3D molecular structures with Caco-2 cell permeabilities, thermodynamic solubilities and metabolic stabilities. Special emphasis will be placed on interpretation of the models by multivariate statistics, because a rational design to improve molecular properties is critically dependent on an understanding of how molecular features influence physico-chemical and ADME properties. 

The use of Caco-2 cell monolayers has gained in popularity as an in vivo human absorption surrogate moreover, the monolayers are generally accepted as a primary absorption screening tool by several pharmaceutical companies [10]. However, Caco-2 cell permeability measurements exhibit certain limitations due to the mechanisms involved. Both passive and active pathways exist active transport tends to increase the absorption across the cells and, since Caco-2 cells overexpress the P-glycoprotein (P-gp) efflux pump, the absorption of some compounds across these cells may be underestimated. 

The applicability range of any model should be limited to molecules having a similar mechanism of transport. Therefore, we have selected from the literature only those compounds with well-characterized Caco-2 cell permeability and excluded compounds with a high efflux ratio. Known P-gp substrates and actively transported compounds were also excluded from the list. 

Table 28.2 IVIVC with Caco-2 Cell Permeability Assays.

J. W. Hirschelman, W. H. et ah Increasing the throughput and productivity of Caco-2 cell permeability assays using liquid chromatography-mass spectrometry application to resveratrol absorption and metabolism. Comb Chem High Throughput Screen 2003, 6, 757-767. 

To meet the need of conducting HTS for ADME-Tox properties, many slow and expensive in vivo ADME assays are now being replaced by in vitro cell models. For intestinal absorption, Caco-2 cell lines and Madin Darby canine kidney (MDCK) cell lines are widely used to predict the absorption rate of candidate drug compounds across the intestinal epithelial cell barrier. A number of models for Caco-2 cell permeability and MDCK cell permeability have been reported that predict the oral absorption properties of drugs, mostly limited to small organic molecules. Caco-2 and MDCK permeability are related to "A" and "D" in the ADME-Tox. 

Castillo-Garit, J.A., Marrero-Ponce, Y., Torrens, F., Garcia-Domenech, R. Estimation of ADME properties in drug discovery predicting Caco-2 cell permeability using atom-based stochastic and non-stochastic linear indices. J. Pharm. Sci. 2008, 97, 1946-76. 

TABLE 6.8 Caco-2 cell permeability of the 13 drugs observed by 3 approaches... 

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