Intestinal transport processes

Enterochromaffin cells are interspersed with mucosal cells mainly in the stomach and small intestine. In the blood, serotonin is present at high concentrations in platelets, which take up serotonin from the plasma by an active transport process. Serotonin is released on platelet activation. In the central nervous system, serotonin serves as a transmitter. The main serotonin-containing neurons are those clustered in form of the Raphe nuclei. Serotonin exerts its biological effects through the activation of specific receptors. Most of them are G-protein coupled receptors (GPCRs) and belong to the 5-HTr, 5-HT2-, 5-HT4-, 5-HTs-, 5-HT6-, 5-HT7-receptor subfamilies. The 5-HT3-receptor is a ligand-operated ion channel. 

In vitro studies permit further isolation of parallel transport processes and can provide a reduction in experimental variability. Rate of absorption assessment can be measured as intestinal uptake or flux across an intestinal barrier at both the tissue and cell monolayer levels. Experimental variability is also reduced by the fact that a large number of tissue samples can be used from the same experi-... 

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]. 

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. 

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... 

From an examination of Tables 7a and b it is apparent that in very young animals there is an increased uptake of actinides across the gastro-intestinal tract. It is known than in suckling animals there is a more rapid accumulation of iron than there is in adult animals. Presumably actinide uptake is a result of entrainment in the iron transporting processes. 

Benet LZ, Wu CY, Hebert MF and Wacher VJ (1996) Intestinal Drug Metabolism and Anti-Transport Processes A Potential Paradigm Shift in Oral Drug Delivery. 

Ruiz-Balaguer N, Nacher A, Casabo VG and Sanjuan MM (2002) Intestinal Transport of Cefuroxime Axetil in Rats Absorption and Hydrolysis Processes. Int J Pharm 234 pp 101-111. 

The intention to study transport processes at pulmonary epithelia, however, raised two particular problems (i) the apical side of these epithelia is typically in contact with air rather than with a liquid and (ii) in order to maximize the surface area, the lungs have a complex treelike structure, ending in millions of tiny alveolar bubbles. The total surface area of the human alveolar epithelium is almost half of that of the intestines (100-120 m2), with its macroscopic appearance resembling a sponge, and it is virtually impossible to use such a tissue for transport experiments in a diffusion-chamber setup. 

Many drugs have been recognized to cross the intestinal epithelial cells via passive diffusion, thus their lipophilicity has been considered important. However, as described above, recent studies have demonstrated that a number of drug transporters including uptake and efflux systems determine the membrane transport process. In this chapter, we provide an overview of the basic characteristics of major drug transporters responsible not only for absorption but also for disposition and excretion in order to delineate the impact of drug transport proteins on pharmacokinetics. 

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