Brain uptake index

The RUI method is a modification of the brain uptake index method [29] which was first described by Aim and Tornquist [4], The RUI approach consists of a single-arterial (e.g., intracarotid) injection technique, where the primary objective is to analyze the influx of the test substrate from the circulating blood to the retina through the BRB (i.e., blood-to-retina direction). This approach, for example, has been used to determine the retinal uptake of the test substrate which has a relatively high permeability across the BRB. The advantage of this approach is that it avoids the effect of plasma-protein binding of the test substrate and allows the retinal uptake of the test substrate... 

Burns and Weaver [6] developed an MLR-based BBB permeability model using two experimental measures of BBB penetrability (brain/plasma ratio and the brain-uptake index) and 14 theoretically derived biophysical predictors based on Stein s hydrogen-bonding number and Randic s topological properties of the molecules. The final model accurately predicted the ability of test molecules to cross the BBB. 

Quantitative measurement of diffusional uptake and carrier-mediated transport of nutrients and drugs in experimental animals was greatly facilitated with the introduction of Olden dorfs brain uptake index (BUI) [42].Test and reference tracers are injected as an intraarterial bolus into the carotid artery of the anaesthetized animal. After 5 s the animal is killed and the brain is removed for radioactivity counting. This method measures the ratio of the unidirectional brain extraction, E, of the test substance and of the reference ([ H]-water, [ " C]-butanol), which are labelled with different isotopes, during a single passage through the brain capillary bed ... 

Moriki, Y., et al. 2004. Involvement of P-glycoprotein in blood-brain barrier transport of pentazocine in rats using brain uptake index method. Biol Pharm Bull 27 932. 

Tang et al.142 studied the effect of chronic hypertension on brain uptake of tryptophan in chronic hypertensive rats and found that brain tryptophan levels were five-fold greater than in normotensive rats. Also, the brain uptake index values for tryptophan were two-fold higher in the experimental rats. 

The fraction of [ N]ammonia extracted by the rhesus monkey brain was found to be independent of ammonia concentration over an 18-fold range in the arterial blood (24), indicating that ammonia enters the brain largely by difiFusion of the free base and not by an active transport system (see also the discussion on the brain uptake index that follows). In the human and the monkey studies, N-activity rapidly approached a maximum in the brain soon after injection of the isotope and thereafter remained fairly constant despite the rapid clearance of the label from the blood (24,25). It was concluded that [ N]ammonia, upon entering the brain, was rapidly metabolized. 

Table I. Brain Uptake Index of [ N] Ammonia Relative to -[l- ]Butyl Alcohol at Two pH Values ...

Table II. Brain Uptake Index for Ammonia Relative...

Figure 9 Effect of cyclosporin A on the brain (A) and plasma (B) concentration of nC verapamil in healthy volunteers. (A) 1 -Verapamil ( 0.2 mCi/kg) was administered to healthy volunteers intravenously, approximately one minute before and after one-hour infusion of cyclosporin A (2.5 mg/kg/h). (B) PET images of a normal human brain after nC-verapamil administration in the absence or presence of cyclosporin A. Images shown are in SUV summed over a period of 5 to 25 minutes, which is an index of regional radioactivity uptake normalized to the administered dose and weight of the subject. Abbreviations PET, positron emission tomography SUV, standardized uptake value. Source From Ref. 218.

A summary of these data on monoamine uptake inhibition and on inhibition of binding by rat brain synaptosomes of the selective 5-HT uptake inhibitor paroxetine and the selective NE uptake inhibitor tomoxetine taken from [53] is shown in table 5. Although the eudismic ratio (potency less active isomer/potency active isomer) of the R and S isomers of fluoxetine is fairly dose to one i.e. 1.58, the selectivity index (antilog (pl 5-HT - Pkj NE) of the S isomer is much larger than that of the R isomer. In offier words the R isomer of fluoxetine is a less selective 5-HT uptake inhibitor than the S isomer but their potendes are similar. This is also confirmed by the data on the inhibition of H-paroxetine and H-tomoxetine binding. 

In vitro dtalopram inhibits H-5-HT uptake in rat brain synaptosomes at an ICso = 1-8 nM and a very high selectivity index (NE/5-HT) versus H-NE uptake of 4888 (Table 10), see the review of Milne and Goa [75] and references dted therein. 

Nitroquipazine (fig. 10) is a potent and highly selective 5-HT uptake blocker in occipitoparietal cortex slices of the rat brain with an ICgo = 81 nM and a selectivity index (NE/5-HT) of 1100 in contrast to its unsubstituted parent compound quipazine which is 65 times less active and nonselective versus NE [86]. 

All of the above-mentioned methods only measure certain indexes of relative permeability for the drug uptake to brain since they cannot determine the driving force for the efflux. Because it is hard to measure the BBB permeability in brain parenchyma, the microvessels in pia dura at the surface of brain (Figure 14.1) are often used in in vivo BBB permeability study. Although pial microvessels do not have the entire ensheathment of astrocytes as those cerebral microvessels in the parenchyma, the pial and cerebral microvessels appear to have many morphophysiological properties in common. These include ultrastructural characteristics, permeability of cell junctions to electron-dense tracers, transendothelium electrical resistance, and molecular properties of endothelium. For these reasons, pial microvessels are often used in the BBB permeability studies [58],... 

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