Permeability Caco-2 model

In comparison to Caco-2 permeability, more models were built to predict log... 

Caco-2 model for permeability Caco-2 permeability vs. human data... 

The HYBOT descriptors were successfully applied to the prediction of the partition coefficient log P (>i--octanol/water) for small organic componnds with one acceptor group from their calculated polarizabilities and the free energy acceptor factor C, as well as properties like solubility log S, the permeability of drugs (Caco-2, human skin), and for the modeling of biological activities. 

Since experimental determination of intestinal absorption is quite demanding, Caco-2 cell monolayers have been successfully used to model passive drug absorption. Several models for the prediction of Caco-2 permeability using PSA were developed, including those of van de Waterbeemd et al. [5] and Palm et al. [22] who found that relationships between Caco-2 permeability and PSA is stronger than with Clog D, Krarup et al. [23] who used dynamic PSA calculated for water accessible molecular surface and Bergstrom et al. [24]. 

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] ... 

We define this permeability as apparent, to emphasize that there are important but hidden assumptions made in its derivation. This equation is popularly (if not nearly exclusively) used in culture cell in vitro models, such as Caco-2. The sink condition is maintained by periodically moving a detachable donor well to successive acceptor wells over time. At the end of the total permeation time f, the mass of solute is determined in each of the acceptor wells, and the mole sum mA (t) is used in Eq. (7.10). Another variant of this analysis is based on evaluating the slope in the early part of the appearance curve (e.g., solid curves in Fig. 7.14) ... 

Since the widely accepted in vitro permeability model in the pharmaceutical industry is based on the use of cultured cells, such as Caco-2 or MDCK, it was appropriate to analyze the regression correlation coefficients based on the comparisons of Caco-2 log Pe and the log Pe values based on the human jejunal measurements [56]. 

The pION double-sink GIT model, with donor pH 5, predicts the human jejunal permeabilities as well as the best reported Caco-2 model (Artursson s), and a lot better than the rest of the reported Caco-2 models, as shown in Fig. 7.63. 

Krishna, G. Chen, K.-J. Lin, C.-C. Nomeir, A. A., Permeability of lipophilic compounds in drug discovery using in-vitro human absorption model, Caco-2, Int. J. Pharm. 222, 77-89 (2001). 

Walter,E. Janich, S. Roessler, B.J. Hilfinger,J.M. Amidon, G. L., HT29-MTX/Caco-2 cocultures as an in vitro model for the intestinal epithelium In vitro-in vivo correlation with permeability data from rats and humans, J. Pharm. Sci. 85, 1070-1076 (1996). 

G Wilson, IF Hassan, CJ Dix, I Williamson, R Shah, M Mackay. Transport and permeability properties of human Caco-2 cells An in vitro model of the intestinal epithelial cell barrier. J Controlled Release 11 25-40, 1990. 

Kim DC, PS Burton, RT Borchardt. (1993). A correlation between the permeability characteristics of a series of peptides using an in vitro cell culture model (Caco-2) and those using an in situ perfused rat ileum model of the intestinal mucosa. Pharm Res 10 1710-1714. 

More than a decade ago, Caco-2 cells grown on permeable supports were introduced as an experimental tool for mechanistic studies of intestinal drug transport [1-4]. At the same time it was suggested that the Caco-2 model was suitable for screening intestinal drug permeability and predicting the oral absorption potential... 

The enthusiasm for using Caco-2 cells and other epithelial cell cultures in studies of drug transport processes has been explained by the ease with which new information can be derived from these fairly simple in vitro models [7]. For instance, drug transport studies in Caco-2 cells grown on permeable supports are easy to perform under controlled conditions. This makes it possible to extract information about specific transport processes that would be difficult to obtain in more complex models such as those based on whole tissues from experimental animals. Much of our knowledge about active and passive transport mechanisms in epithelia has therefore been obtained from Caco-2 cells and other epithelial cell cultures [10-15]. This has been possible since Caco-2 cells are unusually well differentiated. In many respects they are therefore functionally similar to the human small intestinal enterocyte, despite the fact that they originate from a human colorectal carcinoma [16, 17]. 

Fig. 4.1. Relationship between the absorbed vivo perfusion of the human jejunum (B) (data fraction (FA) of structurally diverse sets of compiled from publications by Lennernas orally administered drugs and permeability laboratory [63, 115]). Sigmoidal relationships coefficients obtained in Caco-2 cell monolayers were obtained between FA and the (A) (data compiled from publications by permeability coefficients in both models.

Borchardt. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability, Gastroenterology 1989, 96, 736—749... 

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