Brain blood ratio

There are a number of in vivo methods used to assess brain penetration each with their own benefits and limitations [41]. Much of the in vivo data comes from the brain blood ratio, which is not a direct measure of permeability and therefore is not directly comparable to in vitro permeability values [4]. 

Tryptamines that are unsubstituted on the terminal amine are good substrates for oxidative deamination by MAO. Furthermore, it has been demonstrated that tryptamine and 5-methoxytryptamine cross the blood-brain barrier with great difficulty administration of 50 mg/kg 5-methoxytryptamine to rats results in a low brain/plasma ratio when measured 15 min postadministration (242). 

Granulation and discoloration of kidneys and a decrease in kidney-to-brain-weight ratio was reported in minks fed 6.19 mg/kg/day of heptachlor daily for 28 days (Aulerich et al. 1990). Rats receiving 0.5 mg/kg/day of heptachlor in the diet in an intermediate-duration study showed a statistically significant increase in blood urea (Enan et al. 1982). Increased blood urea may indicate renal inefficiency in metabolism and clearance of protein by-products. This study is limited in that histologic examination was not included in the study design and insufficient dose levels were utilized to establish a dose response. 

H]DMHP was injected intravenously into adult male albino Tuck strain Mo. 1 mice 2" 20 min after administration, the blood brain concentration ratio was 3.7 1. Brain concentration of the drug, on the basis of radioactivity, was approximately 2.5 picograms/gram (pg/g) 15 min after Injection and about 1.7 pg/g at 90 min it slowly decreased to nearly 1.2 pg/g after 16 h. 

PAM crosses the blood-brain barrier with difficulty. 2-PAM in rat brain, 10 min after injection, is only about 5-12% of that in plasma higher percentages are in the more heavily vascularized areas, such as cerebral and cerebellar cortex and inferior colliculi.34 This low brain-to-blood ratio persists, but over the next 6 h the brain and blood come closer to equilibrium as the blood... 

FIGURE 28.3 Effect of Pluronic P85 on the digoxin brain/plasma ratio in the wild-type mice when compared to the mdr la/b (—/—) knockout mouse at 5 h postdose. A tracer dose of [3H]-digoxin (4 p,Ci 7.8 gg/kg) in PBS control or 1% Pluronic P85 solution (100 xL) was administered intravenously into wild-type control group or Pgp knockout mice. Four hours following injection animals were sacrificed and the amount of digoxin in the blood in the brain was assayed. (From Batrakova, E., et al. J. Pharmacol. Exp. Ther., 296, 551, 2001. With permission.)... 

After absorption, cyanide distributes to a volume of approximately 40% total body weight. The distribution is rapid and is completed within 5 min after a single intravenous dose (Sylvester et al, 1983). Cyanide is rapidly transported in the body by blood and about 60% is bound to plasma proteins, a small amount is present in the red blood cells (RBC), and the remainder present as free cyanide (Ryan, 1998). The concentration of cyanide in RBC is estimated to be at a RBC/plasma ratio of 100/1 (Ellenhom et al, 1997). After acute exposures, the plasma elimination half-life of cyanide was observed to be 14.1 min (Egekeze and Oehme, 1979). After oral poisoning, a significant amount of cyanide was traced in the brain, blood, kidney, stomach wall, liver, and urine (Ansell and Lewis, 1970). This indicates that after absorption, cyanide is widely distributed in all the tissues. 

Brewster ME, Pop E, Huang M-J, Bodor N. AMl-based model system for estimation of brain/blood concentration ratios. Int J Quant Chem Quant Biol Symp 1996 23 1775-87. 

Compounds 65 and 66 were prepared as a series of 5-HTg-receptor antagonists. Both indoles exhibited good potency and PK profiles, but had differences in their brain-to-blood ratios. Capping the indole nitrogen with a methyl group (66) reduced the number of hydrogen bond donors and resulted in a brain-to-blood ratio of 2.6, compared to 0.7 for indole 65. 

An interesting question relates to the blood and brain ratios of EPA and DHA. The concentrations of EPA were high in the plasma and low in the brain, with DHA high in both brain and blood. For the erythrocytes, the EPA /DHA was 1.0 for the brain, the ratio was 0.12. It is clear that EPA was metabolized, in contrast to DHA, between the blood compartment and the brain. EPA could have entered the brain and there been converted... 

Fig. 7. Six compounds initially studied for brain penetration by measuring the equilibrium brain/blood concentration ratios of radiolabelled drug in the anaesthetized rat, that is, 16 (icotidine) 17 (SK F 93619), 18 (lupitidine), 19 (clonidine), 20 (mepyramine) and 21...

A few words of caution are required, however. The estimate in vitro of brain/ blood concentration ratios is subject to many errors and has to be regarded as a gross approximatioa Although compounds are administered intravenously by infusion over an extended period (2-3 h) so that near steady state equilibrium is produced, they are subject to different rates of metabolism, elimination (excretion) and protein binding. All these factors will affect the concentration of drag available for brain penetration and will operate differently for each compound. In each case a check was made to determine the proportion of parent drag in the peripheral blood and in the brain by thin-layer chromatography. In most cases, the parent compound was still present at 90% for a few compounds, the proportion of parent present in the blood had decreased to 50%, so that the ratios for these could be underestimated by a factor of up to twofold with respect to metabohsm. 

Compound MEUOES (mgm- ) Vapor pressure (2a C, mmHg) Inhaled dose Proportion absorbed dose absorbed (%) (%) Eliminated Metabolized unchanged Half-life (h) Brain-blood distribution ratio (deaths) Partition coefficient (blood-gas) (37-C)... 

Figure 5. Brain/Blood, Kidneys/Blood, and Liver/Blood Concentration Ratios of HBA after Intravenous Administration of 215.3 umol/kg of HBA with (O ) or without ( ) 3-CD in Male ddY Mice...

After treatment with I, initial organ concentration of titanium was highest in the kidneys 1 h after substance application (Fig. 54). The kidney content of titanium fell during the following hours, while the concentrations in the liver and the intestine increased within 24 h after administration of I and exceeded the kidney values at 4 h and later. At 24 and 48 h, about 10% of total titanium injected was accumulated in the liver corresponding to a liver blood ratio of 8-9. At 96h, the liver blood and intestine blood ratios still amounted to about 5. In the brain, no titanium concentrations higher than control values were measurable at any time during the experimental period, i.e. within four days after substance application. 

A number of carboranyl porphyrins have been obtained on the basis of the natural porphyrin derivatives, such as deuteroporphyrin IX and hematoporphyrin IX, and two of than, VCDP and BOPP (Figure 9.12), have been extensively studied in animals. BOPP was reported to have a tumor-normal brain ratio from 13 1 to 400 1 for different glioma models [117,118]. High boron levels in tumor (>60 pg °B/g tumor) were achieved in these animal studies. However, data obtained from a human Phase I clinical trial showed that under intravenous injection BOPP does not deliver therapeutic concentrations of boron to the tumors of glioblastoma patients, and dose escalation is prevented by the toxicity of this compound. Nevertheless, BOPP has shown some promise as an effective PDT photosensitizer [119-121]. More recently, it was demonstrated that convection-enhanced delivery of BOPP significantly enhances the boron concentration in tumors and produces very favorable tumor-brain and tumor-blood ratios [122]. 

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