Caco prediction

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. 

Human intestinal absorption of 5 (01JPS749) and 6 (01MI30) was predicted by using five Abraham descriptors and CaCo-2 monolayer, respectively. The effect of hydrophobicity and molecular mass on the accumulation of 10 fluoroquinolones, including 5, by Staphylococcus aureus were evaluated (01MI14). 

Respiration of organic matter and dissolution of CaCOs are the main controls of the distribution of deep ocean Total CO2 and alkalinity. These reactions (and their predicted effects on DIC and alkalinity) can be represented schematically as... 

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. 

The importance of drug ionization using cell-based methods such as Caco-2 in the in vitro prediction of in vivo absorption was discussed [45]. It was observed that when the apical pH used in Caco-2 studies was lowered from 7.4 to 6.0 a better correlation was obtained with in vivo data, demonstrating that careful selection of experimental conditions in vitro is crucial to produce a reUable model. Studies with Caco-2 monolayers also suggested that the ionic species might contribute considerably to overall drug transport [46]. 

Avdeef, A., Artursson, P., NeuhofF, S., Lazorova, L., Grasjo, J., Tavelin, S. Caco-2 permeability of weakly basic drugs predicted with the double-sink PAM PA pKl method. Eur.J. Pharm. Sci. 2005, 24, 333-349. 

Absorption of angiotensin II antagonists in Ussing chambers, Caco-2, perfused jejunum loop and in vivo importance of drug ionization in the in vitro prediction of in vivo absorption. Eur. J. Pharm. Sci. 2000, 10, 215-224. 

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]. 

Artursson, P., Palm, K., Luthman, K. Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv. Drug. Ddiv. Rev. 2001, 46, 27-43. 

How Well Do Caco-2 Permeability Measurements Predict Human Jejunal Permeabilities ... 

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. 

Caco-2 Models for Prediction of Human Intestinal Absorption (HIA)... 

In conclusion, the double-sink su m-P, PAMPA in vitro GIT assay seems to predict human absorption as well as in vivo human permeability measurements (see Figs. 7.66a,b) and in vitro Caco-2 permeability measurements (see Figs. 7.60 and 7.63), but at a lower cost and higher speed. 

Yamashita, S. Furubayashi, T. Kataoka, M. Sakane, T. Sezaki, H. Tokuda, H., Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells, Eur. J. Pharm. Sci. 10, 109-204 (2000). 

Pontier, C. Pachot, J. Botham, R. Lefant, B. Amaud, R, HT29-MTX and Caco-2/TC7 monolayers as predictive models for human intestinal absorption Role of mucus layer, J. Pharm. Sci. 90, 1608-1619 (2001). 

In addition, the calculation of many different ID, 2D and 3D descriptors is possible using a range of commercially available software packages, such as Sybyl, Cerius2, Tsar, Molconn-Z and Hybot. Several new descriptor sets are based on quantification of 3D molecular surface properties, and these have been explored for the prediction of, e.g., Caco-2 permeability and oral absorption. It is pointed out here that a number of these new descriptors are strongly correlated to the more traditional physico-chemical properties. 

Caco-2 and Emerging Alternatives for Prediction of Intestinal Drug Transport A General Overview... 

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... 

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