Blood-brain barrier permeability across

Figure 2.5. Setup for in vitro measurement of blood-brain barrier permeability with a co-culture of bovine brain microvascular endothelial cells (BBMEC) and an astro ioma cell line, C6. The BBMEC are grown on top of a filter insert. The C6 cells are either grown on the opposite side of the filter or on the bottom of the wells. Transport across the BBMEC monolayer is measured by adding the test substance to the upper chamber and sampling from the lower chamber. The tightness of the monolayer is also characterized by the transendothelial electrical resistance (TEER). Courtesy of T. Abbruscato.

Absorption Distribution Metabolism Excretion GI tract, lungs, skin Storage in tissues (plasma proteins, liver and kidney, fat, bone), blood-brain barrier, passage across the placenta, membrane permeability Liver, lungs, kidney, brain, phase I, phase II metabolism Urinary, fecal, exhalation, milk, sweat, sahva... 

Specific barriers may serve to limit dmg distribution. The placental barrier is of obvious importance to dmg action in the fetus. Dmg transfers across the placenta primarily by Hpid solubiHty. Hence, this barrier is not particularly restrictive. Similarly, the Hpid solubiHty of a dmg is a primary deterrninant in access to the brain and cerebrospinal fluid. Generally, hydrophilic or charged dmgs can also penetrate to these latter areas, but the result is slow and incomplete. The blood brain barrier is composed of cells having tight junctions which are much less permeable to solutes than are the endotheHal cells of other tissues. 

With disruption of this barrier, molecules such as albumin freely enter the brain and ions and water follow. Because the brain lacks a well-developed lymphatic system, clearance of plasma constituents is slow, edema occurs, and intracranial pressure rises. At lower levels of exposure, subtle dysfunction of the blood-brain barrier may contribute to neurobehavioral deficits in children (Bressler and Goldstein 1991 Goldstein 1993). The particular vulnerability of the fetus and infant to the neurotoxicity of lead may be due in part to immaturity of the blood-brain barrier and to the lack of the high-affinity leadbinding protein in astroglia, which is discussed later in this section. Results of measurements of transendothelial electrical resistance across the blood-brain barrier from mice of various ages showed that lead potentiates cytokines-induced increase in ion permeability of the blood-brain barrier (Dyatlov et al. 

Freshly isolated or subcultured brain microvascular endothelial cells offer a notable in vitro tool to study drug transport across the blood-brain barrier. Cells can be grown to monolayers on culture plates or permeable membrane supports. The cells retain the major characteristics of brain endothelial cells in vivo, such as the morphology, specific biochemical markers of the blood-brain barrier, and the intercellular tight junctional network. Examples of these markers are y-glutamyl transpeptidase, alkaline phosphatase, von-Willebrandt factor-related antigen, and ZO-1 tight junctional protein. The methods of... 

Encephalopathy is a sign of advanced liver disease, either acute or chronic. It usually means that there is altered mechanics across the blood-brain barrier, probably increasing permeability and cerebral blood flow. As a result, patients are more susceptible to CNS side effects of drugs. There is also evidence that the pharmacodynamics, i.e. the receptor sensitivity, of drugs may be altered. 

Chu I, Liu F, Soares A, Kumari P, Nomeir AA. Generic fast gradient liquid chromatography/ tandem mass spectrometry techniques for the assessment of the in vitro permeability across the blood-brain barrier in drug discovery Rapid Common Mass Spectrom 2002 16(15) 1501-1505. 

Poduslo JF, Curran GL, Berg CT. Macromolecular permeability across the blood-nerve and blood-brain barriers. Proc Natl Acad Sci USA 1994 91 5705-5709. 

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