Restricted extracellular space

Following its uptake into the body, the drug is distributed in the blood (1) and through it to the various tissues of the body. Distribution may be restricted to the extracellular space (plasma volume plus interstitial space) (2) or may also extend into the intracellular space (3). Certain drugs may bind strongly to tissue structures, so that plasma concentrations fall significantly even before elimination has begun (4). 

The requirements that must be met to gain the ability to tolerate freezing include the following (1) The formation of true ice is restricted to the extracellular spaces. (2) The formation of ice in the extracellular fluids is not accompanied by extreme dehydration of the cells. (3) Rates of ice crystal formation and the sizes of ice crystals that are generated in the extracellular fluids are held at nonlethal values. (4) Any solid-state water that forms within cells is vitrified water, not true ice. To meet these requirements, freeze-tolerant organisms employ a variety of mechanisms to control the sites, rates, and sizes of ice crystal formation. 

Cerebral edema occurs in response to a wide variety of insults, including ischemia, hypoxia, infection, and noninfectious inflammation. Shifts in brain water, which is the basis of the cellular swelling, are due to osmotic forces, and result in increases in intra- and extracellular spaces. A reasonable amount of tissue swelling can be tolerated in most parts of the body, however, the restrictions imposed by the rigid tentorium and bony skull cause life-threatening herniation with relatively small increases in the brain compartments. Two early anatomists, Monroe (1733-1817) and Kellie (1758-1829), recognized that increased intracranial pressure due to swelling in the cerebrospinal fluid (CSF), blood, or brain tissue compartments could increase intracranial pressure the concept of limited expansion capacity of the intracranial contents is called the Monroe-Kellie doctrine. 

Entry of drugs into the cerebrospinal fluid (CSF) and extracellular space of the central nervous system (CNS) is relatively restricted. The endothelial cells of the CNS have tight junctions and do not have intercellular pores and pinocytotic vesicles. 

Tumor eells ean also present by themselves new MHC elass I-restricted peptides by cross-presentation, a feature believed to be unique of dendritic cells. A peptide derived from secreted matrix metalloproteinase-2 (MMP-2) is presented by melanoma cells, and the presentation is dependent on the enzyme secretion in the extracellular space, followed by uptake of exogenous MMP-2 through endocytosis mediated by integrin avPs. The process involves transfer of MMP-2 from the endocytic compartment to the cytosol and processing by the proteasome, because presentation of this peptide was blocked by proteasome inhibitors [298]. 

If particular pharmacon transport forms are used to facilitate absorption or modulate distribution2 49 51),the requirement is for removal of the disposable moieties introduced, usually by hydrolytic cleavage. If compatible with the desired action as such, an increase in water solubility by introduction of e.g. strongly ionized moieties into the pharmacon molecule may help to restrict distribution to the extracellular space and thus prevent metabolic conversions. 

Fig. 26. The penetration of the acetylcholinesterase inhibitors 217-AO (tertiary base) and 217-MI (quaternary onium compound) in interstitial space and celis in the stellate ganglia (SG) and ciliary ganglia (CG) of cats. The preparations are stained on acetylcholinesterase activity. Note The tertiary compound blocks the enzyme in the extracellular and intracellular space the quaternary onium compound is restricted in its action to the extracellular space. After Mclsaac and Koelle146)...

Previous workers have suggested that the observation of discrete relaxations for intra and extracellular space is a result of the presence of the cell membrane which either restricts the rate of exchange of extracellular water with intracellular bound sites, or provide compartments in idiich the concentration of fast relaxing sites is different. In the light of the results on model systems reported above, the extent to which viable membranes cause multiphasic releixation must be reconsidered, since the presence of extracellular spaces of ft/y dimension may itself cause a significant degree of complex relaxation, whether or not membranes are present or intact. 

Because of their polar nature, the distribution of aminoglycosides is largely restricted to the extracellular space. Consequently, their distribution volume is small both in animals and humans. It equals the volume of the extracellular space or approximately 0.25 L/kg body weight, in normal subjects. 

Mammalian skin is perhaps the most formidable transport barrier found in nature. The lipids of the stratum comeum, the outermost skin layer, form the primary barrier to transport of many compounds of therapeutic interest (Scheuplein, 1965,1978 Potts and Guy, 1992 Blank and Scheuplein, 1969 Elias, 1983,1987,1991). AsshownschematicallyinFig. 2, these lipids form broad multilamellar arrays in the extracellular space surrounding the remains of epidermal cells known as comeocytes. The lipids have a unique composition (fatty acids, cholesterol, and ceramides no phospholipids are present) and form the only continuous domain within the stratum comeum (Elias, 1983, 1987, 1991). Despite profound differences between stratum comeum lipids and those of the phospholipid bilayers more commonly found in other biomembranes, direct comparison of passive transport through each suggests a common mechanism involving Ifee-volume fluctuations in the lipid alkyl chains. Transport within the lipid hydrocarbon domain substantially restricts the permeability of large mol-... 

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