Barrier tissues

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... 

Fromm, M.F. (2004) Importance of P-glycoprotein at blood-tissue barriers. 

Compared to small molecules, barrier opening for high molecular weight compounds is of shorter duration [72]. Furthermore, a characteristic difference exists in the degree of barrier opening in tumour versus normal brain tissue. Barrier disruption was consistently found to be more pronounced for the normal BBB, which may limit the clinical applicability of hyperosmolar barrier opening, at least for cytotoxic drugs [76]. 

Variations on the filter-based assay have been designed to approximate more physiological contexts. Such assays include tumor cell invasion across a confluent cell monolayer (e.g., endothelial cells (EC) as a surrogate for intravasation or extravasation during hematogenous metastasis (24)) and ovarian carcinoma invasion of mesothelial cell monolayers (25). Additionally, 1 mm thick slices of human brain tissue have been used as a tissue barrier on Transwell filters with invasion of GFP-labeled glioma cells measured by confocal microscopy (26). 

Even though subsequent development of visible injury may be as much a property of basic plant metabolism (44), it is necessary that stomata be open during exposure to the gas (42, 43) in order for leaves otherwise potentially ozone-sensitive to manifest injury symptoms. Thus, after the primary tissue barrier to gaseous exchange is traversed, the second barrier is the plasma membrane. Recent work has shown that ozonation can disrupt ion and water flux at the plasma membrane (45, 46), While membrane functional disturbance need not be indiscriminate (25, 46), the cited work supports the suggestion that cellular membranes represent a principal locus of ozone action (10, 39, 47, 48),... 

This is the physicai mass movement of a drug about the site of its administration. Its importance in the production of neurai biockade is not known. It is iikeiy that buik flow is faciiitated in areas where tissue barriers, such as aponeuroses, sheathes, and multiple tissue planes, are minimal. 

Consequently, bioavailability depends on the route of administration as well as the drug s ability to cross membrane barriers. Once in the systemic circulation, further distribution into peripheral tissues may also be important in allowing the drug to reach the target site. Many drugs must eventually leave the systemic capillaries and enter other cells. Thus, drugs have to move across cell membranes and tissue barriers to get into the body and be distributed within the body. In this section, the ability of these membranes to affect absorption and distribution of drugs is discussed. 

A major problem with natural biocompatible materials (collegan, chitosa, etc.) used for tissue barriers is that they absorb water and are permeable to water soluble/... 

P-gp is constitutively expressed in nearly all barrier tissues. Techniques involving Northern blots (37) or Western blots with monoclonal antibodies such as C219 (38) and MRK 16 (39) have been used extensively to determine the tissue distribution of P-gp. It is expressed in adrenal cortex, kidney, liver, intestine, and pancreas endothelial cells at blood-tissue barriers, namely, the CNS, the testis, and in the papillary dermis (3,4,38,40,41). P-gp displays specific subcellular localization in cells with a polarized excretion or absorption function. More specifically, P-gp is found at the apical (AP) canalicular surface of hepatocytes, in the AP membrane of the columnar epithelial cells of colon and jejunum, and the AP brush border of the renal proximal tubule epithelium (3,4,40 1-2). In endothelial cells, P-gp is located in the luminal membrane (4,43). 

In some instances, P-gp can significantly affect the profile of drug distribution from systemic circulation into organs and tissues, most notably those that possess a specialized blood-tissue barrier such as the brain. Experiments with mdrla(—/—) mice have shown how P-gp affects the distribution of its substrates into certain tissues (11,12,124,212-219). A few examples are shown below to demonstrate the role played by P-gp in the tissue distribution of drugs. 

Last, monoclonal antibodies or antibody fragments with specificity for endothelial transport systems (e.g., endosomal pathways) have been proposed as targeting devices to enhance therapeutic drug delivery or overcome tissue barriers [31]. 

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