Permeability blood-brain

Kirkinezos IG, Hernandez D, Bradley WG, Moraes CT (2004) An ALS mouse model with a permeable blood-brain barrier benefits from systemic cyclosporine A treatment. J Neurochem 88 821-826. 

Fagerholm, U. (2007) The highly permeable blood-brain barrier an evaluation of current opinions about brain uptake capacity. Drug Discovery Today, 12, 1076-1082. 

The output from the QikProp is obtained in four files, viz. qikpropameslOO. out, qikpropameslOO.mae, qikpropameslOO.qpsa and qikpropameslOO.csv. Apart from the usual physico-chemical properties, the comma-separated values (CSV) file shows the important descriptors like caco-2 and MDCK cell permeability, blood-brain barrier (logBB), HERG, CNS which are important ADME predicted parameters for a molecule to qualify as drug (Fig. 2.10). 

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. 

The blood-brain barrier (BBB) forms a physiological barrier between the central nervous system and the blood circulation. It consists of glial cells and a special species of endothelial cells, which form tight junctions between each other thereby inhibiting paracellular transport. In addition, the endothelial cells of the BBB express a variety of ABC-transporters to protect the brain tissue against toxic metabolites and xenobiotics. The BBB is permeable to water, glucose, sodium chloride and non-ionised lipid-soluble molecules but large molecules such as peptides as well as many polar substances do not readily permeate the battier. 

Liu X, Tu M, Kelly RS, Chen C and Smith BJ. Development of a computational approach to predict blood-brain barrier permeability. Drug Metab Dispos 2004 32 132-9. 

MW is often taken as the size descriptor of choice, while it is easy to calculate and is in the chemist s mind. However, other size and shape properties are equally simple to calculate, and may offer a better guide to estimate potential for permeability. Thus far no systematic work has been reported investigating this in detail. Cross-sectional area Ad obtained from surface activity measurements have been reported as a useful size descriptor to discriminate compounds which can access the brain (Ad<80A ) of those that are too large to cross the blood-brain barrier (BBB) [55]. Similar studies have been performed to define a cut-off for oral absorption [56]. 

Suomalainen, P., Johans, G., Soderlund, T., Kinnunen, P. K. Surface activity profiling of drugs applied to the prediction of blood-brain barrier permeability. J. Med. Chem. 2004, 47, 1783-1788. 

Dudley, A., Beliveau, R. P-glycoprotein deficient mouse in situ blood-brain barrier permeability and its predicfion using an in comho PAM PA model, (under review)... 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

While evidence of a breakdown in the permeability of the blood-brain barrier in Alzheimer s disease has been presented (Scheibel, 1987), it continues to be a matter of contention (Rozemuller et 1988). 

Oa radicals in arachidonate-induced increased blood-brain barrier permeability to proteins. Am. J. Physiol. 251, H693-699. 

Tanno, H., Nockels, R.P., Pitts, L.H. and Noble, L.J. (1992). Breakdown of the blood brain barrier after fluid percussion brain injury in the rat. 2. Effect of hypoxia on permeability to plasma proteins. J. Neurotrauma, 9, 335-347. 

Whereas the relationship of solute permeability with lipophilicity has been studied in a large number of in vivo systems (including intestinal absorption models [54,55], blood-brain [56 58] and blood nerve [59] barrier models, and cell culture models [60 62], to name just a few), numerous in vitro model systems have been developed to overcome the complexity of working with biological membranes [63-66]. Apart from oil-water systems that are discussed here, the distribution of a solute between a water phase and liposomes is... 

BBB PAMPA Blood brain barrier parallel artificial membrane permeability assay... 

Poduslo JF, Curran GL, Kumar A, Frangione B, Soto C. Beta-sheet breaker peptide inhibitor of Alzheimer s amyloidogenesis with increased blood-brain barrier permeability and resistance to proteolytic degradation in plasma. J Neurobiol 1999 39 371-382. 

PERMEABILITY IN THE GASTROINTESTINAL TRACT AND AT THE BLOOD-BRAIN BARRIER... 

MV Shah, KL Audus, RT Borchardt. The application of bovine brain micro vessel endothelial-cell monolayers grown onto polycarbonate membranes in vitro to estimate the potential permeability of solutes through the blood-brain barrier. Pharm Res 6 624-627, 1989. 

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. 

Dyatlov VA, Platoshin AV, Lawrence DA, et al. 1998. Lead potentiates cytokine- and glutamate-mediated increases in permeability of blood-brain barrier. Neurotoxicology 19 283-292. 

Octanol/water partition (log P) and distribution (log D) coefficients are widely used to make estimates for membrane penetration and permeability, including gastrointestinal absorption [40, 41], blood-brain barrier (BBB) crossing [42, 43], and correlations to pharmacokinetic properties [1], In 1995 and 2000, specialized but very well attended meetings were held to discuss the role of log P in drug research [44, 45]. 

Gumbleton, M. and K. L. Audus. Progress and limitations in the use of in vitro cell cultures to serve as a permeability screen for the blood-brain barrier, J. Pharm. Sci. 2001, 90, 1681-1698... 

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