Blood-brain barrier partition coefficient

Blood-brain barrier partition coefficient Volume of distribution... 

Concerning the distribution of a drug, models have been published for log BB blood/brain partition coefficient) for CNS-active drugs (CNS, central nervous system) crossing the blood-brain barrier (BBB) [38-45] and binding to human serum albumin (HSA) [46]. 

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]. 

The partition coefficient and concepts derived from it are particularly important in explaining the mode of action of neurological drugs, such as anticonvulsants (chapter 8, section 8.1.5) and general anesthetics, which must penetrate the blood-brain barrier prior to exerting their biological effect. 

All inhaled anaesthetic drugs must be soluble in blood and brain in order to pass across the alveolar-capillary membrane and the blood-brain barrier. The term used to quantify solubility is partition coefficient. For anaesthetic purposes this is defined as the ratio of the concentration of dissolved gas/vapour in the blood to the concentration in the alveoli at... 

Lipid soiubiiity is expressed as the octanoi water partition coefficient, its polarity it crosses the blood-brain barrier and undoubtly contributes to the analgesic effect. 

Most log P values are determined with 1-octanol as the nonpolar solvent. Sometimes octanol-water partition coefficients are denoted Pow to make the nonpolar solvent more explicitly clear. Octanol effectively imitates many lipid membranes, especially those in the small intestine, where most drugs are absorbed. Other solvents are better suited to model other tissues in the body. Chloroform is more polar than octanol and simulates partitioning in oral tissues. Olive oil is less polar than octanol and models the blood-brain barrier. 

Figure 5 Illustration of the lock-in mechanism for estradiol-CDS. Octanol-water log partition (log P) and distribution coefficients (log D) are shown to illustrate the significant changes in partition properties. The lipophilic CDS (5) (log P > 4) can easily cross the blood-brain barrier (BBB), but the hydrophilic intermediate (6) (log D < 0) is no longer able to come out providing a sustained release of the active estradiol (7). 

Two compounds had to be excluded from the data set. They were outliers (1.3 log units deviation) as also found in the analysis by Abraham et al. [26], It must also be remembered when considering the derived equations that log BB is a complex parameter that encompasses brain partitioning and permeability and may also depend on other processes such as metabolism, active transport, and so forth. Thus, the standard deviations of these determinations may fall within the range of the mean values. The authors could demonstrate that the derived equation could also estimate log BB outside of the training data set. Therefore, the value of the above correlation with the solvation free energy lies in its power to rank compounds for their ability to cross the blood-brain barrier before synthesis. Interestingly, it was also shown by Lombardo et al. [71] that the calculated AG°W correlated well with the determined permeability coefficient, PC, using endothelial cell monolayers from bovine brain mi-... 

Figure 13.4 The log (blood-brain barrier permeability-surface area (PS) product) is plotted versus the log (partition coefficient) 1 octanol/saline for different molecules of varying molecular weight. The line in bold font denotes the lipid solubility trend line.

On the other hand, atenolol (46), with an octanol/buffer partition coefficient of 0.02 (27), does not cross the blood-brain barrier to any significant extent and is eliminated almost entirely as the unchanged parent drug in the urine and feces. Very small amounts of hydroxylated metabolite (94) and its conjugates have been identified (31), but well over 90% of atenolol is eliminated unchanged. 

The second set of parameters are compound specific and will determine its transport over barriers (e.g., between gut and blood, blood and tissues), its biotransformation, and its excretion. Most of the transport parameters can be described as partition coefficients [20] and are strongly determined by the compound s physicochemical parameters, lipophilicity and volatility being the most important ones. However, the role of transporter proteins present in cellular membranes and responsible for the partitioning over specific barriers needs special attention, e.g., in the gut, the kidney, and at the blood-brain barrier [22], the blood placenta barrier, and the liver-bile interface [23]. 

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