Selected drug transporters

Fig. 4.4. A current trend in drug transport studies is to use simplified cell models that facilitate the characterisation of selected drug transport mechanisms. However, recent research suggests that such simplified systems are not useful in cases where two or more drug transporters act in synergy. Development of cell models for such complex transport mechanisms will require the technically...

TABLE 13.1-2. Selected Drug Transporters Associated with Individual Variations in Drug Response... 

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]. 

Kusuhara, H. and Y. Sugiyama. Role of transporters in the tissue-selective distribution and elimination of drugs transporters in the liver, small intestine, brain and kidney. J. Control. Release 2002, 78, 43-54. 

Cultured nasal cells are reliable models for drug transport and metabolism studies, since they are known to express important biological features (e.g. tight junctions, mucin secretion, cilia, and various transporters), resembling those found in vivo systems. Moreover, easy control of experimental conditions as well as separation of the permeation step from the subsequent absorption cascade is also possible. A relatively simple primary culture condition using human nasal epithelial cells for in vitro drug transport studies has been established and applied in transport and metabolism studies of drugs. It is known that the culture condition and/or selection of culture media are critical in the recapitulation of well-differentiation features of in vivo nasal mucosal epithelium [46],... 

An alternative method for assessing cell layer integrity is through the use of hydrophilic paracellular transport markers (e.g., radiolabeled D-mannitol or fluorescein-Na+), which passively traverse cells by the paracellular route. Small amounts of compound required for in vitro conjunctival cell culture transport experiments make this approach well suited for screening purposes. Relative absorption index of a series of pharmacologically active molecules can be ranked against known markers for the identification of candidates with potential absorption problems, which is a reliable tool to select drug candidates with optimal characteristics. 

Over the last 20 years, the mechanisms of iontophoretic drug transport have been elucidated. In the process, several models have been developed which (a) describe drug transport across the skin under the influence of an electric field, (b) permit drug candidates to be selected rationally, and (c) optimize iontophoretic conditions and formulations. In the first part of this chapter, the main contributions of these models to the field are summarized, and... 

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