Permeability drugs

Artursson P and Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun 1991 175 880-5. 

Stenberg, P., Luthman, K., Artursson, P. Virtual screening of intestinal drug permeability. J. Control. Rel. 2000, 65, 231-243. 

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). 

Gres, M. C. et al. (1998). Correlation between oral drug absorption in humans, and apparent drug permeability in TC-7 cells, a human epithelial intestinal cell line Comparison with the parental Caco-2 cell line. Pharm. Res. 15(5) 726-733. 

Zamora, I., Oprea, T. I., Ungell, A.-L., Prediction of oral drug permeability, in Rational Approaches to Drug Design. Holtje, H.-D., Sippl, W. (eds) Prous Science, Barcelona, 2001, pp. 271-280. 

Most drugs are ionized in aqueous solution (Table 2.1), and can therefore exist in a neutral or a charged state, depending on the pH of the local environment. Molecules are more lipophilic when neutral than when charged. Ionization is expressed by the aqueous ionization constant, pKa. As pointed out below, log D is a p Independent term for ionizable drugs. Permeability and aqueous solubility are also pKa-dependent. Lipophilicity, pKa, permeability through artificial membranes and... 

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... 

Some laboratories have found an alternative to the short-term cultures by using cell lines other than Caco-2 cells. The most popular of these is Madin-Darby canine kidney (MDCK) cells, an epithelial cell line from the dog kidney. MDCK cells have been suggested to perform as well as Caco-2 cells in studies of passive drug permeability [56]. These cells have also been used to optimise the conditions for studies of low-solubility drugs [53]. However, as noted previously, the active transport processes of this cell line can be quite different to those of Caco-2 cells [28-30], Another cell line that only requires short-term culture is 2/4/A1, which is a conditionally immortalised rat intestinal epithelial cell line [86]. The 2/4/A1 cell line is discussed in Section 4.3.2.2 below. 

As for active drug transport, there is no quantitative relationship between passive drug permeability in Caco-2 cells in vitro and drug transport in the human small... 

In the LO phase the optimization of the compounds starts, and eventually ends in the selection of the candidate drug (CD). The strategy with respect to oral drug permeability in this phase of drug discovery is aimed at ... 

Many academic and industrial laboratories have shown that the drug permeability measured in Caco-2 cell monolayers can be used to predict the oral absorption of drugs in humans. Various datasets have therefore been used to establish correlations between Caco-2 permeability and the fraction absorbed orally in humans [85, 86, 96]. Taken together, these studies show good predictability, though with a relatively wide variation in the appearance of correlation profiles between different laboratories [86]. These studies emphasize the need to establish correlations and standardization procedures in each laboratory. 

Passive diffusion through the lipid bilayer of the epithelium can be described using the partition coefficient between octanol/water (log P) and A log P (the difference between the partition into octanol/water and heptane/ethylene glycol or heptane/ octanol) [157, 158], The lipophilicity of the drug (log P) (or rather log D at a certain pH) can easily be either measured or calculated, and is therefore generally used as a predictor of drug permeability. Recently, a method using artificial membrane permeation (PAMPA) has also been found to describe the passive diffusion in a similar manner to the Caco-2 cell monolayers [159]. 

Juliano, R. L., Ling, V., A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants, Biochim. Biophys. Acta 1976, 455, 152-162. 

Fig. 18.1. J-Alert rank correlation for passively the basis of the estimated human effective absorbed drugs only. The ranking of drug permeability (calculated from a 3D structure...

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