Tissue drug transport

An appropriate starting point for any discussion of drug transport in the gastrointestinal (GI) tract at the cellular level requires some introductory remarks on the structure and function of GI tissue. As a class of tissue, epithelia demarcate body entry points (skin, eye, respiratory, urinary, and GI organ systems), predisposing a general barrier function with respect to solute entry and translocation. In addi-... 

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]. 

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. 

Polarized tissues directly involved in drug absorption (intestine) or excretion (liver and kidney) and restricted drug disposition (blood-tissue barriers) asymmetrically express a variety of different drug transporters in the apical or basolateral membrane resulting in vectorial dmg transport. This vectorial dmg transport is characterized by two transport processes the uptake into the cell and subsequently the directed elimination out of the cell (Figure 15.3). Because the uptake of substances... 

This theory was further explored in an anaesthetised pig model, which facilitated portal vein and bile sampling [86], However, the hepatic extraction ratio and the biliary clearance of fexofenadine were unaffected by verapamil in the pig model. The question as to why verapamil/ketoconazole increase the fraction absorbed (i.e. based on appearance kinetics) and yet the fraction absorbed estimated on the basis of disappearance kinetics (i.e. /err) for the intestinal segment appears unchanged remains to be explored and most likely reflect multiple interplay between absorptive and efflux drug transporters in the intestinal tissue. 

The more viable the segment is the better is the quality of the results. Based on the tissue viability data, extremes in permeability values can be discarded from the data set, resulting in better and more reliable results and a better overall understanding of drug transport [108],... 

Ethical issues as well as difficulty in obtaining enough human nasal tissue specimens have called for the need to use alternative in vitro and in vivo methods. Various in vivo animal models and in vitro excised tissue models have been described in the literature for nasal drug transport studies. However, due to the difficulty in both controlling the experimental conditions in in vivo animal models and obtaining intact excised tissue samples, in vitro cell culture models are also being actively developed. 

Because mucin and/or cilia systems of AIC cultured epithelial cells may work as a barrier for drug transport, lower Papp values are expected in cell layers cultured in AIC than in LCC methods. However, it was interesting to note that no significant differences in Rapp values were observed between the cell layers cultured with the two methods (Table 9.1). This is in contrast to solute permeabilities reported previously for cell layers cultured with LCC versus AIC methods [76, 80], For example, Yang et al. reported that Rapp of lipophilic solutes (e.g., various /3-blockers) across the primary cultured conjunctival epithelial cell layer are about threefold lower when cultured under AIC than LCC conditions, suggesting that the permeability of AIC cultured cell layers generally better reflects that of the excised tissue than LCC counterparts. Mathias et al. [76] also reported that the permeability of hydrophilic solutes across the primary rabbit tracheal epithelial cell layer cultured under AIC conditions was only half of that observed for cell layers cultured under... 

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